일주기 리듬, 12시간 리듬(Circasemidian rhythm), 12.4시간 리듬(Circatidal rhythm) 탐구!!

[문형철]

주제 요약

우리가 잘 아는 24시간 주기의 생체시계(일주기 리듬, circadian rhythm) 외에,

최근 연구에서 포유류(쥐·인간 포함)에서 수백 개 유전자가

12시간 주기로 발현된다는 사실이 밝혀졌어요.

이 논문은

이 12시간 리듬(circasemidian rhythm)의 존재,

가능한 생성 메커니즘, 생리적 의미, 그리고

진화적 기원을 정리한 리뷰입니다.

핵심 내용 정리

1. 12시간 리듬이 관찰되는 곳
   • 쥐 간(liver)에서 처음 발견 → 지금은 인간 포함 여러 조직·종에서 확인됨
   • 인간에서는 약 653개 유전자가 12시간 주기로 발현
   • 24시간 리듬 유전자와는 대부분 겹치지 않음 (별개의 패턴)
2. 주요 관련 경로
   • Unfolded Protein Response (UPR): 단백질 접힘 스트레스 대응 경로가 12시간 리듬을 보임
   • 전사인자 XBP1이 핵심 역할 (특히 XBP1s 형태)
3. 어떻게 생기는가? (아직 완전히 풀리지 않은 논쟁 중)
   • 가설 1: 일주기 시계 + 식사/금식 주기(feeding-fasting cycle)가 결합해서 12시간 패턴이 나옴
   • 가설 2: 독립적인 circasemidian oscillator(12시간 전용 시계)가 존재 (BMAL1 독립적, XBP1 중심)
   • 바다 생물의 circatidal rhythm(12.4시간 조석 주기)과 연관성 의심됨
4. 진화적 관점
   • 조류·해양 생물(갑각류, 조개 등)은 조석에 맞춰 12.4시간 리듬을 가짐
   • 육상 포유류의 12시간 리듬이 바다 조상에서 남은 흔적일 가능성
   • 또는 독립적으로 수렴 진화한 것일 수도 있음 (아직 불확실)
5. 인간에게 미치는 의미
   • 12시간 리듬이 깨지면 대사·신경 유지 관련 유전자에 문제 발생
   • 조현병(schizophrenia) 환자에서 12시간 리듬 이상이 관찰됨
   • 비만·대사질환과도 연관 가능성 제기

한 줄 요약

“우리는 24시간으로만 사는 게 아니라,

반나절(12시간) 단위의 생체 리듬도 가지고 있고,

이게 식사 타이밍·단백질 품질 관리·아마도 진화적 바다 유산과 관련이 깊다”는 최신 리뷰

그림 구조 해석 (위에서 아래로)

1. 맨 위: 바다 갑각류 (새우 비슷한 생물, 아마 amphipod나 krill류)
   • Parhyale hawaiensis 같은 해양 갑각류(작은 새우/플랑크톤류)를 상징적으로 그려놓음.
   • 이 생물들은 바다에서 조석(tide)에 맞춰 살아감.
2. 환경 자극 (zeitgebers = 시간 동기화 신호)
   • 왼쪽: 태양(낮) + 달(밤) → 24시간 주기 (빛/어둠 사이클)
   • 오른쪽: 파도(물결) → 조석 주기 (약 12.4시간마다 밀물-썰물 반복)
3. 중간: 두 개의 생체 시계(oscillator)
   • 왼쪽 원: 24h 파형 (sinusoidal wave, 일반적인 circadian clock)
   • 오른쪽 원: 12.4h 파형 (더 빠른 주기)
   • 가운데 화살표(양방향): 두 시계가 진화적으로 연결되거나 전환될 수 있다는 의미 (↔)
4. 아래: 결과로 나오는 리듬
   • Circadian rhythms (24시간 리듬) → 육상 동물(인간·쥐 등)의 기본 생체시계
   • Circatidal rhythms (12.4시간 리듬) → 바다 생물의 조석 적응 리듬

왜 12.4 → 12시간으로 바뀌었을까? (논문 가설)

• 조석 주기 = 정확히 12시간 25분 (지구 자전 + 달 공전 때문에 24시간의 절반이 조금 넘음)
• 육지에서는 조석 영향이 없어지니, 12시간으로 단순화·적응됐을 가능성
• 또는 독립적으로 다시 진화(convergent evolution)했지만, 유전자 패턴(XBP1, UPR 경로)이 바다 생물과 비슷해서 공통 조상 유산으로 보는 시각이 강함.

요약 한 줄 “바다 새우 같은 생물이 조석(12.4h)에 맞춰 산 → 육상 포유류 조상이 그 유산을 물려받아 지금도 반나절(12h) 단위로 몸이 움직인다”는 진화 이야기

맨 위에 쥐(마우스) 아이콘
→ 포유류(특히 쥐) 실험 모델을 상징 아래로 태양/달(light/dark cycle, 24시간 주기 환경 신호)과
Feeding(식사/금식 주기) 화살표가 입력으로 들어감.

그 아래로
24h 파형과 12h 파형이 나오고, "or"로 갈라지면서
세 가지 가능한 생성 메커니즘을 보여줍니다.

1. 왼쪽 모델 (Circadian clock가 둘 다 만듦 – cell-autonomous 방식)

• 입력: 주로 circadian clock (SCN 중심 시계 + 빛/어둠)
• 24h 리듬 → 기본 circadian oscillator (CLOCK/BMAL1 등)가 만듦
• 12h 리듬 → 같은 시계 안에서 antiphase(180도 반대 위상) 전사 조절자 쌍(ROR/REV-ERB 등)이 번갈아 작동 → 12시간마다 유전자 발현 피크가 생김
• 특징: 외부 systemic factor 없이 세포 자율적(cell-autonomous)으로 12h 리듬 생성 가능
• → "Circadian rhythms → Circasemidian rhythms" 화살표로 직접 연결

2. 가운데 모델 (Circadian clock + Feeding/systemic factors 협력 – 가장 지지받는 모델)

• 입력: circadian clock + Feeding (식사 타이밍) + Systemic factors (전신 신호, 예: 호르몬, 대사물, SCN에서 오는 신호)
• 24h 리듬 → 기본 circadian
• 12h 리듬 → circadian clock이 feeding 주기와 결합 → 간(liver) 등 말초 조직에서 12h 패턴이 강화됨
• 예시 증거 (논문 인용):
  • 쥐 간에서 12h 리듬은 feeding이 rhythmic할 때 강하게 나타남
  • clock-deficient (Bmal1 KO) 쥐에서도 feeding 주기가 있으면 12h → 24h로 바뀌거나 feeding phase 피크만 남음
  • 비만이나 feeding 패턴 변화 시 12h 리듬이 깨짐
• → "Circadian rhythms ↓ Circasemidian rhythms" + systemic factors 화살표(빨간색 ↓)

3. 오른쪽 모델 (독립적인 12h oscillator 존재 – dedicated circasemidian clock)

• 입력: circadian clock 영향 최소화
• 24h 리듬 → 기본
• 12h 리듬 → 별도의 12시간 전용 시계가 독립적으로 작동 (BMAL1이나 core clock 독립)
• 핵심 후보: XBP1 (Unfolded Protein Response 경로) 중심 – 단백질 접힘 스트레스, 미토콘드리아, 스트레스 응답 유전자들을 12h 주기로 조절
• 특징: clock-deficient 조직/세포에서도 12h 리듬이 일부 남아 있음 (완전히 사라지지 않음)
• → "Circadian rhythms"와 별도로 "Circasemidian rhythms" 직접 나옴

이 세 모델의 공통점 & 논문 입장

• 세 가지는 mutually exclusive(서로 배타적)이 아님 → 실제로는 조합으로 작동할 가능성이 큼 (논문: non-mutually exclusive)
• 쥐(특히 liver)에서 가장 잘 관찰됨 → 인간에서도 유사 패턴 (653개 유전자 12h 발현)
• 핵심 논쟁: 12h 리듬이 circadian clock의 부산물(harmonic)인지, 아니면 진짜 독립 시계인지 (아직 결론 안 남)
• Feeding(식사 타이밍)이 매우 강력한 zeitgeber(시간 신호)로 작용 → 현대인 불규칙 식사/야간 근무 시 12h 리듬 깨질 수 있음 → 대사·스트레스 질환 연관 가능

한 줄 요약

“쥐 몸속에서 24시간 시계와 12시간 리듬이 같이 도는데,
이 12시간 리듬은
(1) 24시간 시계가 직접 만들거나,
(2) 식사 타이밍+전신 신호와 협력하거나,
(3) 아예 별도 12시간 시계가 있을 수 있다”는
세 가지 가능성을 보여주는 다이어그램이에요.

1. nature  
2. npj biological timing and sleep  
3. review  
4. article

Biological rhythms: Living your life, one half-day at a time

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• Review
• Open access
• Published: 03 June 2025

Biological rhythms: Living your life, one half-day at a time

• Patrick Emery & 
• Frédéric Gachon 

npj Biological Timing and Sleep volume 2, Article number: 21 (2025) Cite this article

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Abstract

Circadian rhythms play a preeminent role in our life, organizing our physiology and behavior on a daily basis to resonate with our fluctuating environment. However, recent studies reveal that hundreds of mouse and human genes are expressed with a 12-h pattern. We take a close look at mammalian 12-h rhythms, their potential mechanisms and functions, and evidence linking them to circatidal rhythms, which enable marine animals to adapt to tides.

일주기 리듬은

우리 삶에서 지배적인 역할을 담당하며,

매일 우리의 생리 기능과 행동을 조율하여 끊임없이 변하는 환경과 조화를 이루도록 합니다.

그러나

최근 연구에서 쥐와 인간을 포함한 포유류에서

수백 개의 유전자가 12시간 주기로 발현되는 패턴이 밝혀졌습니다.

본 리뷰에서는

포유류의 12시간 리듬을 면밀히 살펴보고,

그 가능한 생성 메커니즘과 생리적 기능,

그리고 해양 생물이 조석에 적응하게 하는 circatidal 리듬과의 연관성을 제시하는 증거들을

종합적으로 논의합니다.

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Introduction

Life on Earth is profoundly impacted by various environmental cycles of defined periodicities. Organisms cope with them with the help of biological clocks that closely match the period of the cycle they track1. Circadian (~24 hour [h]) clocks allow organisms to optimize their physiology and behavior with the time-of-day. For example, most of us humans sleep during the night and are active during the day. Our sleep/wake and feeding/fasting cycles, as well as many other rhythmic physiological processes, are coordinated by circadian pacemaker neurons located in the suprachiasmatic nucleus (SCN) of the hypothalamus. These neurons synchronize cell-autonomous circadian clocks present throughout our body, which regulate locally rhythmic gene expression‎2. At the molecular level, the core circadian molecular clock in animals is a negative transcriptional feedback loop that comprises the heterodimeric transcriptional activator Circadian Locomotor Output Cycles Kaput/Brain and Muscle ARNT-like 1 (CLOCK/BMAL1) and its own repressor complex, which, depending on the species, may contain Period (PER), Timeless (TIM) and/or Cryptochrome (CRY) proteins2,3. This core loop is interlocked with a second transcriptional loop that generates a wave of transcription with an opposite phase2. This second loop contains the transcription factors Vrille (VRI) and PAR-Domain-Protein 1 (PDP1) in fruit flies, and RAR-Related Orphan Receptor (ROR)/REV-ERB proteins in mammals.

Other biological timers can play key roles in adaptation to ever-changing environmental conditions, but they are not as well understood1. Circannual (~1 year) clocks are critical for seasonal adaptation, such as the timing of migration, hibernation, and reproduction. Circalunar clocks (~29.5 days) keep track of the phase of the moon and play a particularly important role for the timing of reproduction in the sea. Finally, circatidal clocks allow marine organisms to anticipate the changes linked with the 12.4-h tidal cycle (water level, food availability, currents, temperature, etc.)4,5. Interestingly, there is growing evidence that ca. 12-h rhythms are not limited to marine animals. They have also been observed in cyanobacteria6, diatoms7 and even in terrestrial animals such as Drosophila8,9, C. elegans10, mice10,11,12,13,14,15,16,17,18, and most recently in humans13,19. It has been proposed that 12-h rhythms (or circasemidian rhythms) in terrestrial animals are related to circatidal rhythms10,11,12,13. After introducing these ca. 12.4-h marine rhythms, this review focus on 12-h rhythms in terrestrial mammals, their potential mechanisms, and their role in physiology and human health.

서론 (Introduction)

지구상의 생명은

다양한 정의된 주기를 가진 환경 주기에 깊이 영향을 받는다.

생물들은

자신이 추적하는 주기와 거의 일치하는 생물 시계(biological clocks)의 도움을 받아

이러한 주기에 대처한다¹.

일주기(~24시간) 시계는

생물들이 하루 중 시간에 따라 생리와 행동을 최적화할 수 있게 한다.

예를 들어,

우리 인간 대부분은 밤에 잠을 자고 낮에 활동한다.

우리의 수면/각성 주기, 섭식/금식 주기,

그리고 많은 다른 리듬적인 생리 과정들은

시상하부의 시교차상핵(SCN)에 위치한 일주기 페이스메이커 뉴런들에 의해 조정된다.

이 뉴런들은

우리 몸 전체에 존재하는 세포 자율적(cell-autonomous) 일주기 시계를 동기화시키며,

이는 국소적으로 리듬적인 유전자 발현을 조절한다².

분자 수준에서 동물의 핵심 일주기 분자 시계는

음성 전사 피드백 루프(negative transcriptional feedback loop)로,

이형이합체 전사 활성제 Circadian Locomotor Output Cycles Kaput/Brain and Muscle ARNT-like 1 (CLOCK/BMAL1)과

그 자신의 억제 복합체로 구성되며,

종에 따라 Period (PER), Timeless (TIM), 그리고/또는

Cryptochrome (CRY) 단백질을 포함할 수 있다²,³.

이 핵심 루프는

반대 위상(opposite phase)의 전사 파동을 생성하는

두 번째 전사 루프와 상호 연결되어 있다².

이 두 번째 루프는 초파리(fruit flies)에서는

전사인자 Vrille (VRI)와 PAR-Domain-Protein 1 (PDP1)을,

포유류에서는 RAR-Related Orphan Receptor (ROR)/REV-ERB 단백질을 포함한다.

다른 생물 타이머들도

끊임없이 변화하는 환경 조건에 적응하는 데 중요한 역할을 할 수 있지만,

아직 잘 이해되지 않았다¹.

연주기(~1년) 시계는

계절 적응에 필수적이며,

이동, 동면, 번식 시기 등을 결정한다.

월주기(~29.5일) 시계는

달의 위상을 추적하며,

특히 바다에서 번식 시기를 조절하는 데 중요한 역할을 한다.

마지막으로,

조석 주기 시계(circatidal clocks)는

해양 생물이 12.4시간 조석 주기(수위, 먹이 가용성, 해류, 온도 등)와

관련된 변화를 예측할 수 있게 한다⁴,⁵.

흥미롭게도,

약 12시간 리듬은 해양 동물에만 국한되지 않는다는 증거가 점점 늘고 있다.

이는 남조류(cyanobacteria)⁶, 규조류(diatoms)⁷,

그리고 심지어 육상 동물인 초파리(Drosophila)⁸,⁹, C. elegans¹⁰, 쥐(mice)¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,

그리고 가장 최근에는 인간¹³,¹⁹에서도 관찰되었다.

육상 동물의 12시간 리듬(또는 circasemidian 리듬)이

circatidal 리듬과 관련이 있다는 제안이 있었다¹⁰,¹¹,¹²,¹³.

이 약 12.4시간 해양 리듬을 소개한 후, 본 리뷰는

육상 포유류의 12시간 리듬,

그 잠재적 메커니즘, 그리고 생리 및 인간 건강에서의 역할을 중점적으로 다룬다.

Circatidal clocks

In 1903, the French biologist Georges Bohn brought back beach sand containing a green acoelomate: the Roscoff’s worm. Bohn had noticed that this simple animal, which contains a symbiotic micro-algea, sinks into the sand before the arrival of tides to avoid dispersion. After placing the collected sand in an elongated glass tube, Bohn observed a green ring moving down the tube in anticipation of tides, and moving back up when the low tide would have occurred at the beach of origin20. Since this seminal report of a circatidal rhythm, the nature of the circatidal clock has been hotly debated. Naylor proposed that circatidal rhythms are driven by a dedicated 12.4 -h oscillator21,22, but because the period of circatidal rhythms is so close to half that of the circadian clock, Enright instead proposed that a single clock would drive either circadian or circatidal rhythms, depending on the environmental cycles an animal is exposed to23. The period would be adjusted from 24 h to 24.8 h in the presence of tides, with two peaks of activity generated every 12.4-h. Finally, Palmer and Williams proposed the existence of a circatidal clock comprised of two coupled antiphase 24.8-h oscillators that would generate 12.4-h rhythms of activity24,25.

In coastal insects and crustaceans, behavioral studies strongly support the existence of distinct circadian and circatidal clocks (Fig. 1): circatidal rhythms of behavior can be modulated as a function of the time-of-day even under constant conditions, while circadian behavior can show circatidal influence (reviewed in ref. 4). Hybrid behaviors are observed in the amphipod Parhyale hawaiensis under naturally occurring diurnal or mixed tidal regimen, which deviate significantly from the most common regular 12.4-h tidal cycle26. Moreover, pioneer studies in the crustacean Eurydice pulchra and the mangrove cricket Apteronemobius asahinai further support the idea that circadian and circatidal clocks are distinct: circatidal rhythms of behavior were unaffected by knocking down two essential circadian genes, per27,28 and Clock29, through the abdominal injection of specific dsRNAs to trigger RNA interference (RNAi). Recently, however, two studies found that another essential circadian clock gene, Bmal1, is required for circatidal behavior. One study relied again on RNAi in E pulchra30, while the other used CRISPR/Cas9 mutagenesis to generate a null allele of Bmal1 in the amphipod P. hawaiensis31. In the latter organism, both circadian and circatidal rhythms were disrupted by loss of Bmal1. This indicates some mechanistic overlap between circadian and circatidal clocks. A recent manuscript actually raises the possibility that the mechanistic overlap is broader than expected from RNAi studies32, which have a significant caveat: the incomplete suppression of gene expression‎. Indeed, ca. 12-h rhythms of per and cry2 mRNAs were observed in a subset of clock neurons in P. hawaiensis animals entrained to rhythmic vibrations mimicking tides, while most clock neurons showed a circadian pattern of gene expression‎. The existence of distinct circadian and circatidal neurons would explain how rhythmic behavior can be both under circadian and circatidal control in this organism26.

조석 주기 시계 (Circatidal clocks)

1903년,

프랑스 생물학자 조르주 본(Georges Bohn)은 해변 모래를 가져왔는데,

그 안에 녹색 무체강동물인 Roscoff’s worm(로스코프 벌레)이 포함되어 있었다.

본은 이 단순한 동물이 공생 미세조류를 가지고 있으며,

조수가 오기 전에 모래 속으로 가라앉아 분산을 피한다는 사실을 알아챘다.

수집한 모래를 긴 유리관에 넣은 후, 본은 조수가 도착하기 전에 녹색 고리가 관 아래로 이동하고, 원래 해변에서 썰물이 될 때쯤 다시 위로 올라오는 것을 관찰했다²⁰. 이 획기적인 circatidal 리듬 보고 이후, circatidal 시계의 본질은 뜨거운 논쟁의 대상이 되었다. 네일러(Naylor)는 circatidal 리듬이 전용 12.4시간 발진기(oscillator)에 의해 구동된다고 제안했으나²¹,²², circatidal 리듬의 주기가 일주기 시계의 절반에 매우 가깝기 때문에, 엔라이트(Enright)는 단일 시계가 동물이 노출된 환경 주기에 따라 일주기 또는 circatidal 리듬을 구동한다고 제안했다²³. 조수가 있을 때는 주기가 24시간에서 24.8시간으로 조정되며, 매 12.4시간마다 활동 피크가 두 번 생성된다는 것이다. 마지막으로, 팔머(Palmer)와 윌리엄스(Williams)는 circatidal 시계가 두 개의 결합된 반위상(antiphase) 24.8시간 발진기로 구성되어 있으며, 이는 12.4시간 활동 리듬을 생성한다고 제안했다²⁴,²⁵.

연안 곤충과 갑각류에서 행동 연구는 별개의 일주기 시계와 circatidal 시계의 존재를 강력히 지지한다(Fig. 1): 상수 조건 하에서도 circatidal 행동 리듬은 하루 중 시간에 따라 조절될 수 있으며, 일주기 행동은 circatidal 영향을 받을 수 있다(참고문헌 4에서 리뷰됨). 자연적으로 발생하는 주간 또는 혼합 조석 조건 하에서 양서류(amphipod) Parhyale hawaiensis에서 하이브리드 행동이 관찰되며, 이는 가장 흔한 규칙적인 12.4시간 조석 주기에서 크게 벗어난다²⁶. 또한, 갑각류 Eurydice pulchra와 맹그로브 귀뚜라미 Apteronemobius asahinai에 대한 선구적 연구는 일주기와 circatidal 시계가 구별된다는 아이디어를 더욱 뒷받침한다: 특정 dsRNA를 복부 주사하여 RNA 간섭(RNAi)을 유발함으로써 두 개의 필수 일주기 유전자 per²⁷,²⁸과 Clock²⁹을 knockdown했음에도 circatidal 행동 리듬은 영향을 받지 않았다. 그러나 최근 두 연구에서는 또 다른 필수 일주기 시계 유전자 Bmal1이 circatidal 행동에 필요하다는 사실을 발견했다. 한 연구는 다시 E. pulchra에서 RNAi를 사용했으며³⁰, 다른 연구는 amphipod P. hawaiensis에서 CRISPR/Cas9 돌연변이를 이용해 Bmal1의 null allele을 생성했다³¹.

후자 생물에서는

Bmal1의 상실로 일주기와 circatidal 리듬 모두가 파괴되었다.

이는 일주기와 circatidal 시계 사이에 일부 기계적 중첩(mechanistic overlap)이 있음을 나타낸다.

최근 한 논문은 RNAi 연구에서 예상보다 기계적 중첩이 더 광범위할 수 있다는 가능성을 제기했다³².

RNAi 연구에는 유전자 발현의 불완전 억제라는 중요한 한계가 있기 때문이다.

실제로, 조석을 모방하는 리듬적 진동에 적응된 P. hawaiensis 동물에서 per와 cry2 mRNA의 약 12시간 리듬이 일부 시계 뉴런에서 관찰되었으며, 대부분의 시계 뉴런은 일주기 패턴의 유전자 발현을 보였다. 별개의 일주기 뉴런과 circatidal 뉴런의 존재는 이 생물에서 리듬적 행동이 일주기와 circatidal 제어를 동시에 받을 수 있는 이유를 설명할 수 있다²⁶.

Fig. 1: Circadian (~24 h) and circatidal (~12.4 h) rhythms coexist in crustaceans.

In P. hawaiensis, interacting circadian and circatidal clocks are entrained by the light/dark and tidal cycles, respectively, to control rhythmic behavior. See main text for details. Created in BioRender. Emery, P. (2025) https://BioRender.com/caeejhf.

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That per and cry2 might flexibly adopt 12.4 h or 24 h period of expression‎ in P. hawaiensis is reminiscent of observations made in oysters. In these marine animals, circadian clock genes can show either 24-h or 12.4-h rhythms of expression‎, depending on whether animals are exposed to tides or only to a LD cycle33. The circatidal clock might thus have considerable mechanistic overlap with the circadian clock. Alternatively, circadian gene expression‎ might be driven by a circatidal clock functioning upstream of the circadian clock. The development of novel models and genetic approaches to study circatidal rhythms will hopefully soon help elucidate the molecular mechanisms underlying circatidal clocks4.

Circadian or circatidal control of ~ 12-h rhythms?

Distinguishing circadian from circatidal rhythms can be challenging, both at the behavioral and molecular level, because their periodicities are so close to be harmonics. Genes under circadian clock control could be expressed with a 12-h period if their promoters or enhancers harbor binding sites for both the CLOCK/BMAL1 heterodimer and the transcription factors involved in the second transcriptional feedback loop, or other pairs of regulators active in antiphase17,34. Accordingly, the overlapping BMAL1/REV-ERBα/REV-ERBβ cistrome (genome-wide binding sites) contains a few rhythmic genes with a 12-h period expression‎ pattern35. Nevertheless, the majority of the genes in this common cistrome presented a circadian pattern of expression‎, suggesting that such dual 12-h regulation is limited, at least for genes co-regulated by ROR/REV-ERB and CLOCK/BMAL1 transcription factors.

In addition, the circadian clock can generate 12-h rhythms non-cell-autonomously. For example, 12-h rhythms in the mouse liver appear to be dependent on both the local circadian clock and external signaling, presumably from the central circadian pacemaker in the SCN (Fig. 2, see also below)18. At the behavioral level, the circadian clock can generate two bouts of activity per day. For example, Drosophila melanogaster presents two daily activity peaks in the morning and evening, ca. 12 h apart. These peaks are controlled by two different set of circadian pacemaker neurons, referred to as Morning and Evening oscillators36,37. Both harbor the same circadian clock mechanism, but these neurons are either more active in the morning or in the evening38.

Fig. 2: Circadian (~24 h) and circasemidian (~12 h) rhythms coexist in mice.

Both circadian and circasemidian rhythms of gene expression‎ can be observed in mice (in whole animals or cell lines). They might be generated through three, non-mutually exclusive, mechanisms. Left: the circadian clock generates both 24 h and 12 h rhythms. Circasemidian rhythms could be the result of two distinct sets of transcriptional regulators taking turn to promote gene expression‎ every 12 h (double arrow). Middle: the circadian clock collaborates with systemic factors controlled by feeding to generate circasemidian rhythms. Right: a dedicated 12-h oscillator, independent of the circadian clock, generates circasemidian rhythms, reminiscent of the independent circadian and circatidal clocks in crustaceans (see Fig. 1). Created in BioRender. Emery, P. (2025) https://BioRender.com/n22k1pa.

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A key criterion to determine whether a ca. 12-h rhythm in a marine organism is driven by the circadian or the circatidal clock is to test if that rhythm is entrained (synchronized) by the light/dark (LD) cycle or by the tides. In the lab, the phase of the tidal cycle can be shifted, and a circatidal molecular or behavioral rhythm will shift accordingly (see for example31,32). In the field, animals can be collected at different periods of the lunar month (e.g.39). Ideally constant conditions should be used to ensure that the observed rhythms are not direct responses to environmental changes.

Beginning with the mussel Mytilus californianus40, multiple transcriptomics studies have been aimed at identifying genes under circatidal control (e.g.40,41,42,43,44,45,46). To our knowledge however, no such work has so far been designed to meet both key criteria for circatidal rhythms: that the rhythms in the 12-h range free-run and that tides entrain them. This is understandable given the cost and challenges of circatidal transcriptomics studies, particularly in the field, but it is important to keep in mind that at least some of the 12-h oscillations might not actually be circatidal. This issue is particularly acute when 12-h rhythms are designated as, or proposed to be, “circatidal” in animals exposed to LD cycles, in the complete absence of tidal input47,48. To briefly summarize these transcriptomics studies, it appears that hundreds to thousands of genes might be under circatidal control. Genes implicated in transcription, ER function, proteostasis, and metabolism are frequently expressed with a 12-h rhythm4.

The ultimate way to distinguish a circadian rhythm from a circatidal rhythm would be to determine whether a behavioral or molecular rhythm is eliminated when either the circadian or the circatidal clock is genetically disrupted. Combining RNAi or CRISPR/Cas9 gene editing with transcriptomics would be a powerful way to elucidate the mechanism underlying 12-h rhythms in marine organisms. Unfortunately, no gene dedicated to circatidal rhythms has been isolated in any species so far. However, as mentioned above, RNAi studies in crustaceans and insects targeting core circadian genes (per, cry2, and Clock) suggest that circatidal behavior is independent of the circadian clock27,28,29,30. If these observations are confirmed with stringent genome-editing methods, this should open a path to determine whether 12-h transcriptional rhythms persist after disruption of the circadian clock.

12-h rhythms of gene expression‎ in mice

Soon after the initial identification of ca. 12-h rhythms of gene expression‎ in mussels40, similar pattern of expression‎ were unexpectedly discovered in mice. Taking advantage of then-recently developed transcriptomics technologies, Hughes et al. characterized hundreds of 12-h period genes in the liver and other organs17. Under constant darkness condition, the two daily peaks of expression‎ were centered around two critical circadian markers: the beginning of the resting (subjective light) phase and the beginning of the active (subjective dark) phase. Further studies showed that the rhythmic activation of the Unfolded Protein Response (UPR), a signal transduction pathway adjusting critical cellular function to the accumulation of proteins inside the endoplasmic reticulum (ER)49, plays a critical role in the generation of murine circasemidian rhythms of gene expression‎, suggesting a transcription-led mechanism10,11,14,17. Nevertheless, recent evidence also demonstrates the additional role of mRNA degradation in the generation of 12-h rhythms of gene expression‎50.

A key question is whether murine 12-h rhythms are driven by the circadian clock or a dedicated circasemidian oscillator. The harmonic nature of the two oscillations again complicates matters. Early investigations indicated that systemic factors, combined with local circadian clocks, determine hepatic circasemidian rhythms (Fig. 2). Like circadian rhythms 12-h rhythms are maintained in constant darkness. However, the phase and amplitude of these rhythms are impacted by obesity and feeding rhythms, themselves controlled by the central circadian pacemaker14,17,18,51. As expected, several studies demonstrated the disappearance of the expression‎ of 12-h rhythmic genes in clock deficient animals or cell cultures14,17,18,50,51,52. However, these 12-h rhythmic genes were expressed with a 24-h rhythm in circadian mutant animals when rhythmic feeding was maintained using time-restricted feeding or by restoring a functional circadian clock in the brain of clock-deficient animals14,17,18,52. Interestingly, only the peak associated with the dark/feeding phase was present.

Thus, based on these studies, it appears that murine 12-h rhythms are the results of a combination of food-related cues and local circadian regulation (Fig. 2). However, recent work by Bokai Zhu and collaborators challenges this conclusion10,11,53. This team has presented evidence for a dedicated cell-autonomous circasemidian oscillator, independent of BMAL1 and thus the circadian clock (Fig. 2). This pacemaker would be organized around XBP1, a key transcription factor in one of the branches of the UPR10,11,53. Accordingly, a large number of 12-h rhythmic genes were associated with the UPR and included genes involved in protein processing in the ER ang Golgi apparatus. In addition, circasemidian rhythms were found in other fundamental cellular processes such as mitochondrial activity, mRNA translation, cell cycle, and interferon/NF-kB pathways10,11,17.

The nature of the murine circasemidian oscillator is currently unclear. Liver-specific elimination of XBP1 significantly decreased the number of 12-h rhythmic transcripts in this organ, but circasemidian rhythms were far from abolished. Some RNAs even saw the amplitude of their 12-h rhythms increasing in the absence of XBP111. Thus, this transcription factor does not appear to be an essential part of the putative Bmal1-independent circasemidian oscillator, but rather an important downstream effector. It will be very important to figure out the root causes for the different conclusions reached on the role of circadian genes such as Bmal1 in the control of murine 12-h rhythms. Is it the use of different cell lines (MEFs10 vs primary hepatocytes, U2OS17, or NIH3T350), animal care, or statistical methods used to identify rhythmic genes? Could both the circadian clock and a distinct circasemidian oscillator generate 12-h rhythms? Clearly, much additional research is required to decipher how circasemidian rhythms are generated in mice.

12-h rhythms in humans

Recent studies indicate that 12-h rhythms in transcript level are also present in humans. In a very original study published in NJP Biological Timing and Sleep, Zhu and collaborators measured gene expression‎ patterns in three volunteers13. Blood samples were collected over 48-h, and the transcriptome of peripheral blood cells was analyzed at high temporal resolution. As expected, thousands of genes showed an expression‎ pattern in the circadian range (5453 genes to be precise), but a significant number showed rhythms in the circasemidian range (653). Importantly, Zhu et al. provide evidence that these genes are not simply controlled by the circadian clock. First, the average period of circadian and circasemidian genes is not a perfect harmonic. Second, the identity and functions of the two pools of genes are clearly different. These results thus support the existence of two different oscillatory mechanisms for ca. 12-h and 24-h rhythms. Interestingly, based on the meta-analysis of the three patients, the circasemidian rhythms appear to involve the UPR transcription factor XBP1, suggesting a conserved mechanism between mouse and human.

However, working with human subject comes with important limitations. The Zhu et al. study was not performed under constant conditions13. The volunteers received meals at specific times of the day and were in control of lightning in their environment. The time at which they switched off or on the lights, when precisely they ate, or when they fell asleep, was not reported. This is significant, particularly considering the impact of feeding rhythm on the activation of the UPR pathway18,51. Indeed, a very striking observation in this study is the remarkably tight phase distribution of rhythmic transcripts in each individual, but also the interindividual variability of phase. It would have been important to know what the volunteers were doing and when to determine whether their 12-h rhythms in gene expression‎ were linked to behavioral, internal or environmental cues. At the very least, such cues might have contributed to the tight phase distribution. They could even be entirely responsible for the observed rhythms. The latter does not seem likely, however. Indeed, the genes that were 12-h rhythmic showed significant overlap with circasemidian transcripts in mouse liver11,17. Importantly, this mouse study was performed under constant conditions, and the distribution of transcript phase was much broader than in the human study.

Are circatidal and terrestrial 12-h rhythms evolutionarily related?

The similarity of 12-h rhythmic genes in humans and mice suggests a conserved underlying mechanism. Zhu et al.13 present evidence for an even deeper evolutionary connection as they found a statistically significant overlap with 12-h rhythms in a cnidarian: A. diaphana47. It would be really fascinating if mammalian 12-h rhythms are evolutionary remnants of marine circatidal rhythms, as the authors proposed. Such connection would be conceivable given the marine ancestry of tetrapod. However, we do not think that such conclusion is warranted yet. First, that genes implicated in splicing, protein synthesis, protein homeostasis, and fatty acid metabolism are regulated by a 12-h oscillator in mammals and Cnidarian could be the result of convergent evolution, given their critical importance for cell metabolism and physiology. Second, the expression‎ studies in A. diaphana were performed under LD conditions, not tidal conditions47. As discussed above, this is a really important caveat, as it is unclear whether the 12-h rhythms observed are driven by a circadian or a circatidal clock, or even simply light-driven. The phase of the rhythmic transcripts in A. diaphana was, as in the human study, very tight, suggesting that acute response to the light cycle at least partially contributed to the observed rhythms. A previous study by Zhu et al. also compared murine circasemidian transcription with a second marine organism, which was exposed to both tides and a LD cycle: the limpet C. rota39. Again, there was significant overlap between the limpet and mouse 12-h rhythms, and the limpet study was based on time series generated at two different time of the lunar month. Thus, the 12-h rhythms observed were synchronized to the tides, not the LD cycle. It would have been interesting to determine whether the conservation of 12-h transcripts between the limpet and mouse extends to humans. There is further indication of an ancient origin for 12-h rhythms. 12-h oscillations in UPR-related genes have been broadly found among living species, including invertebrates9,10,40,54, cnidarian47,48, diatom7, and cyanobacteria6. However, most of these studies were conducted under rhythmic environmental conditions, and such apparent conservation could again be the result of convergent evolution.

In summary, whether there is an evolutionary connection between 12-h rhythms in mammals and circatidal rhythms in marine organisms remains uncertain. Determining the mechanisms of these ultradian oscillations is therefore critical. We know that circatidal behavioral rhythms are dependent on Bmal1 in P. hawaiensis31 and E. pulchra30, but RNAi studies in the latter suggest a separate mechanism for circatidal rhythms independent of per27 or cry230. In mammals, as mentioned above, different studies have come to different conclusions on the necessity of Bmal1 and the circadian clock for 12-h rhythms. While XBP1 seems to be an important contributor, other factors appear also involved, as observed for the UPR. Thus, reconciling contradicting conclusions in mammals and uncovering the mechanism of the marine circatidal clock will help answering the fundamentally important questions of the evolutionary origin of 12-h rhythms.

One can wonder why terrestrial animals would need ca. 12 h rhythms in gene expression‎ since they are not subjected to tides. This might be simply the result of the day or night length averaging 12-h. In mice, the two peaks of gene expression‎ correspond to the beginning of the fasting and feeding periods linked to their rhythmic behavior and physiology. Many animals, including Drosophila as mentioned above, are crepuscular and thus are active with a 12-h period. It is therefore possible that physiological phenomena happening 12 h apart independently activate the UPR and require increased protein synthesis and maturation as Zhu et al. proposed in their “rush hour” hypothesis11.

A recent study identified 12-h rhythms in transcript levels in brain samples from deceased controls and schizophrenic patients19. Curiously, there was a preferential disruption of these 12-h rhythms in the patient cohort, particularly for mRNAs encoding genes of the UPR response and involved in neuronal maintenance. It is unclear whether these rhythmic disruptions are relevant to the etiology of the disease or are a mere consequence of it. Even so, such disruption could contribute to the disease symptoms and thus be clinically relevant. Moreover, as discussed, metabolic conditions also impact 12-h rhythms in mice. It is therefore urgent to shed light on the mechanism underlying these rhythms, which until recently had been overlooked.

Data availability

No datasets were generated or analyzed during the current study.

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