Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock.
DNA binding
FRAP
cell biology
chromosomes
circadian
gene expression
live-cell imaging
modelling
mouse
single cell quantification
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
14 03 2022
14 03 2022
Historique:
received:
16
09
2021
accepted:
11
03
2022
pubmed:
15
3
2022
medline:
8
4
2022
entrez:
14
3
2022
Statut:
epublish
Résumé
The mammalian circadian clock exerts control of daily gene expression through cycles of DNA binding. Here, we develop a quantitative model of how a finite pool of BMAL1 protein can regulate thousands of target sites over daily time scales. We used quantitative imaging to track dynamic changes in endogenous labelled proteins across peripheral tissues and the SCN. We determine the contribution of multiple rhythmic processes coordinating BMAL1 DNA binding, including cycling molecular abundance, binding affinities, and repression. We find nuclear BMAL1 concentration determines corresponding CLOCK through heterodimerisation and define a DNA residence time of this complex. Repression of CLOCK:BMAL1 is achieved through rhythmic changes to BMAL1:CRY1 association and high-affinity interactions between PER2:CRY1 which mediates CLOCK:BMAL1 displacement from DNA. Finally, stochastic modelling reveals a dual role for PER:CRY complexes in which increasing concentrations of PER2:CRY1 promotes removal of BMAL1:CLOCK from genes consequently enhancing ability to move to new target sites.
Identifiants
pubmed: 35285799
doi: 10.7554/eLife.73976
pii: 73976
pmc: PMC8983044
doi:
pii:
Substances chimiques
ARNTL Transcription Factors
0
CLOCK Proteins
EC 2.3.1.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/P017355/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107851/Z/15/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U105170643
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM107069
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/P017347/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R35 GM141849
Pays : United States
Organisme : Wellcome Trust
ID : 216416/Z/19/Z
Pays : United Kingdom
Informations de copyright
© 2022, Koch et al.
Déclaration de conflit d'intérêts
AK, JB, NS, NB, AA, JF, DS, QM, CP, KS, TH, MH, AL No competing interests declared
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