The circadian demethylation of a unique intronic deoxymethylCpG-rich island boosts the transcription of its cognate circadian clock output gene

Abstract

We demonstrate that there is a tight functional relationship between two highly evolutionary conserved cell processes, i.e., the circadian clock (CC) and the circadian DNA demethylation–methylation of cognate deoxyCpG-rich islands. We have discovered that every circadian clock-controlled output gene (CCG), but not the core clock nor its immediate-output genes, contains a single cognate intronic deoxyCpG-rich island, the demethylation–methylation of which is controlled by the CC. During the transcriptional activation period, these intronic islands are demethylated and, upon dimerization of two YY1 protein binding sites located upstream to the transcriptional enhancer and downstream from the deoxyCpG-rich island, store activating components initially assembled on a cognate active enhancer (a RORE, a D-box or an E-box), in keeping with the generation of a transcriptionally active condensate that boosts the initiation of transcription of their cognate pre-mRNAs. We report how these single intronic deoxyCpG-rich islands are instrumental in such a circadian activation/repression transcriptional process.

The HP1α protein is mandatory to repress the circadian clock and its output genes during the 12 h period of transcriptional repression

“…S4 B ). Note that this transfer of repressive components from a repressed enhancer to an intronic CpG island is carried out through a mechanism which is similar to that observed upon gene transactivation, as shown in our accompanying PNAS paper entitled “The circadian demethylation of a unique intronic deoxymethylCpG-rich island boosts the transcription of its cognate circadian clock output gene” ( 19 ).…”

Blood DNA methylation in post-acute sequelae of COVID-19 (PASC): a prospective cohort study

“… 49 Notably, binding of BMAL1 and other members of the bHLH family are sensitive to DNA methylation, and circadian rhythm per se is associated with alterations in DNA methylation. 50 , 51 , 52 Abnormal circadian rhythm has been associated with perturbed inflammatory response, 53 , 54 and more recently, with PASC. 55 , 56 , 57 Interestingly, while recent evidence indicates that reduced intestinal absorption of the serotonin precursor tryptophan could be related to the neurocognitive deficits of PASC, 58 alterations of the intestinal microbiome leading to disruption of absorptive mechanisms have been attributed to circadian rhythm dysregulation as well.…”

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

“…Interestingly, some active enhancers seem not to display elevated contact frequency with any gene, in a given cell type, albeit displaying high enrichment of active enhancer features (72). A strikingly similar sequence of events may also be observed on a shorter time scale, for instance for domains that switch between A and B compartments over a circadian cycle (97)(98)(99), or upon neuron stimulation and memory encoding (100). Thus, there is strong evidence that DHS/enhancers mediate domain opening, enabling promoter activation, but also recombination and initiation of DNA replication (101,102), and conceivably any process that is inhibited by heterochromatin in the B compartment, in an indirect and therefore nonspecific manner.…”

“…Loss of DNA methylation is assumed to aid in the DNA binding of TFs, but strikingly it appears not to be an absolute prerequisite for DNA binding of a large number of TFs, even factors known to be methylation-sensitive. It may occur either before, or concomitantly, or with some delay relative to the appearance of a DHS, the first option being characteristic of sites bound by certain pioneer factors such as Klf4 (99,117,251,289,290).Only in a distinct, final stage, coinciding with the onset of gene transcription, chromatin marks typical of active enhancers or active promoters appear at the corresponding DHS, while not at other DHS, which are dubbed "primed enhancers". Fig.…”