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Collapse of the hepatic gene regulatory network in the absence of FoxA factors

The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the disp...

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Autores principales: Reizel, Yitzhak, Morgan, Ashleigh, Gao, Long, Lan, Yemin, Manduchi, Elisabetta, Waite, Eric L., Wang, Amber W., Wells, Andrew, Kaestner, Klaus H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397852/
https://www.ncbi.nlm.nih.gov/pubmed/32561546
http://dx.doi.org/10.1101/gad.337691.120
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author Reizel, Yitzhak
Morgan, Ashleigh
Gao, Long
Lan, Yemin
Manduchi, Elisabetta
Waite, Eric L.
Wang, Amber W.
Wells, Andrew
Kaestner, Klaus H.
author_facet Reizel, Yitzhak
Morgan, Ashleigh
Gao, Long
Lan, Yemin
Manduchi, Elisabetta
Waite, Eric L.
Wang, Amber W.
Wells, Andrew
Kaestner, Klaus H.
author_sort Reizel, Yitzhak
collection PubMed
description The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the adult mouse liver. Remarkably, loss of FoxA caused rapid and massive reduction in the expression of critical liver genes. Activity of these genes was reduced back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining enhancer activity, chromatin accessibility, nucleosome positioning, and binding of HNF4α. Thus, the FoxA factors act continuously, guarding hepatic enhancer activity throughout adult life.
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spelling pubmed-73978522021-02-01 Collapse of the hepatic gene regulatory network in the absence of FoxA factors Reizel, Yitzhak Morgan, Ashleigh Gao, Long Lan, Yemin Manduchi, Elisabetta Waite, Eric L. Wang, Amber W. Wells, Andrew Kaestner, Klaus H. Genes Dev Research Paper The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the adult mouse liver. Remarkably, loss of FoxA caused rapid and massive reduction in the expression of critical liver genes. Activity of these genes was reduced back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining enhancer activity, chromatin accessibility, nucleosome positioning, and binding of HNF4α. Thus, the FoxA factors act continuously, guarding hepatic enhancer activity throughout adult life. Cold Spring Harbor Laboratory Press 2020-08-01 /pmc/articles/PMC7397852/ /pubmed/32561546 http://dx.doi.org/10.1101/gad.337691.120 Text en © 2020 Reizel et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Reizel, Yitzhak
Morgan, Ashleigh
Gao, Long
Lan, Yemin
Manduchi, Elisabetta
Waite, Eric L.
Wang, Amber W.
Wells, Andrew
Kaestner, Klaus H.
Collapse of the hepatic gene regulatory network in the absence of FoxA factors
title Collapse of the hepatic gene regulatory network in the absence of FoxA factors
title_full Collapse of the hepatic gene regulatory network in the absence of FoxA factors
title_fullStr Collapse of the hepatic gene regulatory network in the absence of FoxA factors
title_full_unstemmed Collapse of the hepatic gene regulatory network in the absence of FoxA factors
title_short Collapse of the hepatic gene regulatory network in the absence of FoxA factors
title_sort collapse of the hepatic gene regulatory network in the absence of foxa factors
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397852/
https://www.ncbi.nlm.nih.gov/pubmed/32561546
http://dx.doi.org/10.1101/gad.337691.120
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