RT Journal Article
SR Electronic
T1 Dynamic enhancer partitioning instructs activation of a growth regulator during exit from naïve pluripotency
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 441824
DO 10.1101/441824
A1 Maxim V.C. Greenberg
A1 Aurélie Teissandier
A1 Marius Walter
A1 Daan Noordermeer
A1 Deborah Bourc’his
YR 2018
UL http://biorxiv.org/content/early/2018/10/12/441824.abstract
AB During early mammalian development, the genome undergoes profound transitions in chromatin states, topological organization and recruitment of cis regulatory factors involved in transcriptional control. How these three layers of gene regulation interact is the matter of intense research. The Zdbf2 gene—which is involved in growth control—provides a valuable model to study this question: upon exit from naïve pluripotency and prior to tissue differentiation, it undergoes a switch in usage from a distal to a proximal promoter, along with a switch in chromatin states, from polycomb to DNA methylation occupancy. Using an embryonic stem cell (ESC) culture system to mimic this period, we show here that four enhancers contribute to the Zdbf2 promoter switch, concomitantly with dynamic changes in chromosome architecture. Indeed, CTCF plays a key role in partitioning the locus in ESCs, to facilitate enhancer contact with the distal Zdbf2 promoter only. Partition relieving enhances proximal Zdbf2 promoter activity, as observed during differentiation or with mutants that lack local CTCF-based partition. Importantly, we show that CTCF-based regulation occurs independently of the polycomb and DNA methylation pathways. Our study reveals the importance of multi-layered regulatory frameworks to ensure proper spatio-temporal activation of developmentally important genes.