Chromatin modifications shape cell heterogeneity by activating and repressing defined sets of genes involved in cell proliferation, differentiation and development. Polycomb-repressive complexes (PRCs) act synergistically during development and differentiation by maintaining transcriptional repression of common genes. PRC2 exerts this activity by catalysing H3K27 trimethylation. Here, we show that in the intestinal epithelium PRC2 is required to sustain progenitor cell proliferation and the correct balance between secretory and absorptive lineage differentiation programs. Using genetic models, we show that PRC2 activity is largely dispensable for intestinal stem cell maintenance but is strictly required for radiation-induced regeneration by preventing Cdkn2a transcription. Combining these models with genomewide molecular analysis, we further demonstrate that preferential accumulation of secretory cells does not result from impaired proliferation of progenitor cells induced by Cdkn2a activation but rather from direct regulation of transcription factors responsible for secretory lineage commitment. Overall, our data uncover a dual role of PRC2 in intestinal homeostasis highlighting the importance of this repressive layer in controlling cell plasticity and lineage choices in adult tissues.

PRC2 preserves intestinal progenitors and restricts secretory lineage commitment / F. Chiacchiera, A. Rossi, S. Jammula, M. Zanotti, D. Pasini. - In: EMBO JOURNAL. - ISSN 0261-4189. - 35:21(2016), pp. 2301-2314. [10.15252/embj.201694550]

PRC2 preserves intestinal progenitors and restricts secretory lineage commitment

S.G. Jammula;D. Pasini
2016

Abstract

Chromatin modifications shape cell heterogeneity by activating and repressing defined sets of genes involved in cell proliferation, differentiation and development. Polycomb-repressive complexes (PRCs) act synergistically during development and differentiation by maintaining transcriptional repression of common genes. PRC2 exerts this activity by catalysing H3K27 trimethylation. Here, we show that in the intestinal epithelium PRC2 is required to sustain progenitor cell proliferation and the correct balance between secretory and absorptive lineage differentiation programs. Using genetic models, we show that PRC2 activity is largely dispensable for intestinal stem cell maintenance but is strictly required for radiation-induced regeneration by preventing Cdkn2a transcription. Combining these models with genomewide molecular analysis, we further demonstrate that preferential accumulation of secretory cells does not result from impaired proliferation of progenitor cells induced by Cdkn2a activation but rather from direct regulation of transcription factors responsible for secretory lineage commitment. Overall, our data uncover a dual role of PRC2 in intestinal homeostasis highlighting the importance of this repressive layer in controlling cell plasticity and lineage choices in adult tissues.
chromatin modifications; H3K27 methylation; intestinal homeostasis and differentiation; polycomb; PRC2; Animals; Cell Differentiation; Cell Proliferation; Embryonic Stem Cells; Histones; Intestinal Mucosa; Mice, Transgenic; Polycomb Repressive Complex 2; Neuroscience (all); Molecular Biology; Immunology and Microbiology (all); Biochemistry, Genetics and Molecular Biology (all)
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
Settore BIO/10 - Biochimica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/562737
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