Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity

Abstract

The rapid renewal of intestinal epithelium is mediated by a pool of stem cells, located at the bottom of crypts, giving rise to highly proliferative progenitor cells, which in turn differentiate during their migration along the villus. The equilibrium between renewal and differentiation is critical for establishment and maintenance of tissue homeostasis, and is regulated by signaling pathways (Wnt, Notch, Bmp…) and specific transcription factors (TCF4, CDX2…). Such regulation controls intestinal cell identities by modulating the cellular transcriptome. Recently, chromatin modification and dynamics have been identified as major actors linking signaling pathways and transcriptional regulation in the control of intestinal homeostasis. In this review, we synthesize the many facets of chromatin dynamics involved in controlling intestinal cell fate, such as stemness maintenance, progenitor identity, lineage choice and commitment, and terminal differentiation. In addition, we present recent data underlying the fundamental role of chromatin dynamics in intestinal cell plasticity. Indeed, this plasticity, which includes dedifferentiation processes or the response to environmental cues (like microbiota’s presence or food ingestion), is central for the organ’s physiology. Finally, we discuss the role of chromatin dynamics in the appearance and treatment of diseases caused by deficiencies in the aforementioned mechanisms, such as gastrointestinal cancer, inflammatory bowel disease or irritable bowel syndrome.

Regulatory domains controlling high intestinal vitamin D receptor gene expression are conserved in mouse and human

“…( 23 ) found that binding motifs for CDX2, HNF4a/g, and GATA 4/5/6 were enriched in 4575 ATAC-Seq peaks that are seen in intestine but not in other tissues. Among these, CDX2 is viewed as a master regulator of intestinal epithelial cell identity ( 24 ) that maintains a permissive chromatin environment that favorably influences the DNA binding of other TFs, for example, the intestine restricted TF HNF4a ( 25 ). Similarly, SMAD4 and HNF4 activate each other's expression and cobind to regulatory elements of intestinal differentiation genes to stabilize enterocyte identity ( 26 ), whereas other evidence shows that GATA4 is critical for gene expression in the proximal small intestine ( 27 ).…”

Cdx2 Regulates Intestinal EphrinB1 through the Notch Pathway

“…Homeostasis of the intestinal epithelium requires coordinated interaction between numerous signaling pathways and transcription factors [ 43 ]. Cdx2 has been linked to regulation of expression of genes in the Notch signaling pathway [ 44 ], including Dll1 [ 13 , 21 ].…”

“…Taken together, our observations lead to a model wherein Cdx impacts EphrinB1 expression and the CRC phenotype via a Notch-dependent mechanism (Figure 7). Homeostasis of the intestinal epithelium requires coordinated interaction between numerous signaling pathways and transcription factors [43]. Cdx2 has been linked to regulation of expression of genes in the Notch signaling pathway [44], including Dll1 [13,21].…”

“…Cdx2 has been linked to regulation of expression of genes in the Notch signaling pathway [44], including Dll1 [13,21]. Homeostasis of the intestinal epithelium requires coordinated interaction between numerous signaling pathways and transcription factors [43]. Cdx2 has been linked to regulation of expression of genes in the Notch signaling pathway [44], including Dll1 [13,21].…”

Control of intestinal stemness and cell lineage by histone variant H2A.Z isoforms

“…Chromatin dynamics is crucial for organ development, including the control of proliferation, cell fate determination and tissue homeostasis, as well as for its plasticity and adaptive abilities to stresses (Rispal et al ., 2020). The role of chromatin components in the establishment of genetic programs controlling tissue homeostasis is a very partially explored field.…”