eprintid: 10108540
rev_number: 16
eprint_status: archive
userid: 608
dir: disk0/10/10/85/40
datestamp: 2020-09-02 15:23:28
lastmod: 2021-12-05 01:04:09
status_changed: 2020-09-02 15:23:28
type: article
metadata_visibility: show
creators_name: Baulies, A
creators_name: Angelis, N
creators_name: Foglizzo, V
creators_name: Danielsen, ET
creators_name: Patel, H
creators_name: Novellasdemunt, L
creators_name: Kucharska, A
creators_name: Carvalho, J
creators_name: Nye, E
creators_name: De Coppi, P
creators_name: Li, VSW
title: The Transcription co-Repressors MTG8 and MTG16 Regulate Exit of Intestinal Stem Cells From Their Niche and Differentiation into Enterocyte vs Secretory Lineages
ispublished: inpress
divisions: UCL
divisions: B02
divisions: D13
divisions: G22
keywords: chromatin remodeling, lateral inhibition, lineage specification, niche exit
note: © 2020 by the AGA Institute. Published by Elsevier Inc. under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).
abstract: BACKGROUND & AIMS: Notch signaling maintains intestinal stem cells (ISCs). When ISCs exit the niche, Notch signaling among early progenitor cells at position +4/5 regulates their specification toward secretory vs enterocyte lineages (binary fate). The transcription factor ATOH1 is repressed by Notch in ISCs; its de-repression, when Notch is inactivated, drives progenitor cells to differentiate along the secretory lineage. However, it is not clear what promotes transition of ISCs to progenitors and how this fate decision is established. METHODS: We sorted cells from Lgr5-Gfp knock-in intestines from mice and characterized gene expression patterns. We analyzed Notch regulation by examining expression profiles (by quantitative reverse transcription PCR and RNAscope) of small intestinal organoids incubated with the Notch inhibitor DAPT, intestine tissues from mice given injections of the γ-secretase inhibitor dibenzazepine, and mice with intestine-specific disruption of Rbpj. We analyzed intestine tissues from mice with disruption of the RUNX1 translocation partner 1 gene (Runx1t1, also called Mtg8) or CBFA2/RUNX1 partner transcriptional co-repressor 3 (Cbfa2t3, also called Mtg16), and derived their organoids, by histology, immunohistochemistry, and RNA sequencing. We performed chromatin immunoprecipitation and sequencing analyses of intestinal crypts to identify genes regulated by MTG16. RESULTS: The transcription co-repressors MTG8 and MTG16 were highly expressed by +4/5 early progenitors, compared with other cells along crypt-villus axis. Expression of MTG8 and MTG16 were repressed by Notch signaling via ATOH1 in organoids and intestine tissues from mice. MTG8- and MTG16-knockout intestines had increased crypt hyperproliferation and expansion of ISCs, but enterocyte differentiation was impaired, based on loss of enterocyte markers and functions. Chromatin immunoprecipitation and sequencing analyses showed that MTG16 bound to promoters of genes that are specifically expressed by stem cells (such as Lgr5 and Ascl2) and repressed their transcription. MTG16 also bound to previously reported enhancer regions of genes regulated by ATOH1, including genes that encode delta-like canonical Notch ligand and other secretory-specific transcription factors. CONCLUSIONS: In intestine tissues of mice and human intestinal organoids, MTG8 and MTG16 repress transcription in the earliest progenitor cells to promote exit of ISCs from their niche (niche exit) and control the binary fate decision (secretory vs enterocyte lineage) by repressing genes regulated by ATOH1.
date: 2020-06-15
date_type: published
official_url: https://doi.org/10.1053/j.gastro.2020.06.012
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1794153
doi: 10.1053/j.gastro.2020.06.012
pii: S0016-5085(20)34764-8
lyricists_name: De Coppi, Paolo
lyricists_id: PDECO50
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Gastroenterology
event_location: United States
citation:        Baulies, A;    Angelis, N;    Foglizzo, V;    Danielsen, ET;    Patel, H;    Novellasdemunt, L;    Kucharska, A;                 ... Li, VSW; + view all <#>        Baulies, A;  Angelis, N;  Foglizzo, V;  Danielsen, ET;  Patel, H;  Novellasdemunt, L;  Kucharska, A;  Carvalho, J;  Nye, E;  De Coppi, P;  Li, VSW;   - view fewer <#>    (2020)    The Transcription co-Repressors MTG8 and MTG16 Regulate Exit of Intestinal Stem Cells From Their Niche and Differentiation into Enterocyte vs Secretory Lineages.                   Gastroenterology        10.1053/j.gastro.2020.06.012 <https://doi.org/10.1053/j.gastro.2020.06.012>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10108540/1/1-s2.0-S0016508520347648-main.pdf