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Review
. 2020 Dec;16(6):1062-1080.
doi: 10.1007/s12015-020-10055-0. Epub 2020 Oct 13.

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

Jérémie Rispal  1 , Fabrice Escaffit  2 , Didier Trouche  1
Affiliations
Review

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

Jérémie Rispal et al. Stem Cell Rev Rep. 2020 Dec.

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. Graphical abstract.

Keywords: Chromatin remodeler; Differentiation; Epigenetics; Histone post-translational modification; Homeostasis; Intestinal epithelium; Lineage commitment; Response to environment; Stem cell proliferation.

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Conflict of interest statement

Conflict of Interest. The authors declare no conflict of interest.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Dynamics of chromatin modification during ISC differentiation. A At the promoter of ISC signature genes, main changes in chromatin modification during enterocytes differentiation are loss of H3K4me3 and H3K27ac, correlated with loss of gene expression. B At the promoters of approximately 400 enterocyte signature genes, H2A.Z is lost during differentiation, correlating with a gain in gene expression. Noted that H3K4me3 and H3K27ac are either already present, or added to these promoters. Moreover, there is also a loss of H3K27me3 at the promoters of a few enterocyte signature genes, such as Cdkn2a/b
Fig. 2
Fig. 2
Model for H2A.Z1’s role in the maintaining proliferative abilities and precluding differentiation. In the crypt, high Wnt activity favors the expression of the H2A.Z1 encoding gene (H2afz). Thus, H2A.Z1 participates in cell proliferation, and is also incorporated at the promoters of differentiation genes, where it inhibits the binding of the transcription factor CDX2 and thereafter gene expression. During cell migration along the villus, reduction in Wnt activity leads to a decrease in H2A.Z1 expression. This variant is then removed from the chromatin, allowing CDX2 binding and the expression of CDX2-target differentiation genes
Fig. 3
Fig. 3
Role of chromatin modifiers in intestinal epithelial homeostasis. A In stemness. Many chromatin modifiers are essential for ISC maintenance. Deletion of PRC2, HDAC1/2 or ZNHIT1-containing SRCAP complex leads to loss of ISC and greatly impairs formation of organoids in 3D culture conditions. SWI/SNF complexes are also involved in this process, since ARID1a-containing complex promotes Sox9 expression and since BRG1-containing complex directly favors Lgr5, Olfm4 and Ascl2 expression. DNMT1 is involved in restricting stemness by inhibiting expression of stem cell markers like Olfm4, Sox9 and Msi1. B Progenitor identity. PRC2 and HDAC are essential for maintaining undifferentiated features of progenitor cells. Indeed, both modifiers favor cell proliferation through Cdkn2a (Ink4) inhibition and p21 expression, and inhibit expression of differentiation genes. DNMT1 and DNMT3b are also involved in maintaining progenitor proliferation. In contrast, MBD3-containing NuRD complex is involved in restricting proliferative cells in the crypt compartment. C Wnt pathway regulation. Tip60, by suppressing β-CATENIN acetylation, inhibits proliferation of intestinal cells, whereas the p400 complex has the opposite effect, by promoting expression of Wnt target genes. CBP and p300 HATs promote expression of Wnt target genes by recruiting β-CATENIN/TCF4 transcription factors. D Lineage choice. PRC2 and SWI/SNF complex containing BRG1 help determine specific lineage during progenitor cell maturation. Indeed, both complexes inhibit commitment to the secretory lineage by repressing Atoh1/Math1 expression, which promotes the absorptive fate. E Secretory differentiation. SWI/SNF complex containing ARID1a is also involved in secretory lineage differentiation. Indeed, although the temporal and spatial requirements of this complex for this lineage differentiation are unknown, all secretory cells are lost in the KO mice. F Enteroendocrine differentiation. The two HATs, p300 and PCAF, are involved in differentiation of enteroendocrine cells, by promoting expression of NEUROD1 target genes, especially Secretin gene. G Enterocyte differentiation. p300/CBP seems to be involved in enterocyte differentiation. Indeed, recruitment of these 2 HATs is correlated with an increase in expression of the CRBPII coding gene, which is involved in Vitamin A transport and metabolism in enterocytes. In contrast, PRC2 complex is involved in repressing enterocyte differentiation by inhibiting expression of genes like SI, LPH or ALPI
Fig. 4
Fig. 4
Chromatin remodeling during dedifferentiation. The Lgr5+ ISC loss is followed by dedifferentiation of progenitor cells to maintain tissue renewal. Dedifferentiation of secretory cells could require global chromatin remodeling, in which PRC2, but also other chromatin modifiers, could be necessary. On the other hand, very similar DNA accessibility profiles between ISC and absorptive cells suggest dedifferentiation from absorptive cells without any global chromatin remodeling. Thus, this way could be easier or faster, increasing the probability of such an event, which could already be favored by the high number of cells engaged in enterocyte lineage
Fig. 5
Fig. 5
Model of the control of intestinal cell circadian physiology by microbiota via the chromatin modifications. A Intestinal commensal microbiota induce signals promoting intestinal cells to integrate them. At the molecular level, these signals lead to the recruitment of HDAC3 at specific gene promoters, to regulate expression of these genes in a circadian manner, essential for the digestive physiology. HDAC3 is recruited at the end of the day, due to differential microbiota composition and quantity depending of the circadian cycle phase (Thaiss et al., 2016), and then deacetylates histones and thus inhibits gene expression. B In germ-free mice, absence of microbiota and their signals lead to loss of HDAC3 recruitment. Histone acetylation and gene expression levels are consistently high during all of the circadian cycle, leading to loss of rhythmicity. Note that graphics schematically summarize HDAC3 recruitment, histone acetylation and gene expression of all genes in this study
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