RT Journal Article
SR Electronic
T1 Intestinal stem cell differentiation is associated with dynamic changes in the chromatin landscape
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 637181
DO 10.1101/637181
A1 Jesse R Raab
A1 Kortney E Wager
A1 Jeremy M Morowitz
A1 Scott T Magness
A1 Adam D Gracz
YR 2019
UL http://biorxiv.org/content/early/2019/05/23/637181.abstract
AB Chromatin is central to cellular identity and is remodeled as stem cells differentiate and acquire mature cell fates. In the adult intestinal epithelium, functional plasticity facilitates de-differentiation and reacquisition of stemness by progenitors and some post-mitotic cell types following damage to the intestinal stem cell (ISC) pool. Previous studies have suggested that this plasticity is regulated by largely homogenous or “static” chromatin landscapes shared by ISCs and their progeny. Here, we utilize a Sox9EGFP reporter mouse to examine native chromatin across the continuum of ISC differentiation. Our data reveal a highly dynamic chromatin landscape in IECs, associated mainly with open chromatin regions (OCRs) found in intergenic or intragenic loci consistent with putative distal enhancers. By integrating gene expression with chromatin accessibility at transcription factor (TF) binding motifs in context of Sox9EGFP populations, we classify “static” and “dynamic” chromatin relative to specific TF usage. These analyses identify known and potential regulators of ISC differentiation via their association with dynamic changes in chromatin and suggest that differential cis- and trans-regulatory significance can be defined in a locus-specific manner. Finally, we apply the Sox9EGFP model to examine the relationship between gene expression and a specific chromatin modification, 5-hydroxymethylcytosine (5hmC), which reveals a role for 5hmC in absorptive lineage specification. Together, our data demonstrate a previously unappreciated degree of global chromatin changes in intestinal epithelial cells (IECs), identify novel potential regulators of ISC differentiation, and provide a chromatin roadmap for further dissecting the role of cis regulation of cell fate in the intestine.