ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
- Institut National de la Santé et de la Recherche Médicale, France
- Assistance Publique Hôpitaux de Paris, France
- University of Michigan, United States
Abstract
Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice genetically-invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of Arid1a together with β-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.
Data availability
Microarrays have been deposited in GEO database (GSE134553) and are publicly available.All data generated or analysed during this study are included in the manuscript and supporting files. Source data excel files have been provided for Figures 1, 2, 3, 4, 5, 7, 8, 1S1,1S3,3S1,5S1,5S2,7S1.
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Expression data from isolated areas from [Apc-Arid1a]ko-focal liver tissues after FFPE treatmentNCBI Gene Expression Omnibus, GSE134553.
Article and author information
Author details
Funding
Institut National Du Cancer (Epigenetics and Liver Cancer)
- Rozenn Riou
- Angélique Gougelet
- Cécile Godard
- Julien Calderaro
- Sabine Colnot
Ligue Contre le Cancer (Equipe Labellisée)
- Rozenn Riou
- Angélique Gougelet
- Cécile Godard
- Sabine Colnot
Agence Nationale de la Recherche (Labex Who Am I"; Idex "EpilivCan"")
- Rozenn Riou
- Angélique Gougelet
- Cécile Godard
- Sabine Colnot
Institut National Du Cancer (Chromaliv)
- Rozenn Riou
- Angélique Gougelet
- Cécile Godard
- Sabine Colnot
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the French government regulations. All of the animals were handled according to approved institutional animal care and use committee (Ethics Committee of Descartes University, Paris). The protocol was approved by the Ethics Committee of Descartes University, Paris (permit number APAFIS#14472). Every effort was made to minimize suffering.
Copyright
© 2020, Riou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription
eLife 9:e53550.
https://doi.org/10.7554/eLife.53550
Further reading
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- Cell Biology
- Chromosomes and Gene Expression
During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme – the senescence-associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.
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- Chromosomes and Gene Expression
- Evolutionary Biology
Gene regulation is essential for life and controlled by regulatory DNA. Mutations can modify the activity of regulatory DNA, and also create new regulatory DNA, a process called regulatory emergence. Non-regulatory and regulatory DNA contain motifs to which transcription factors may bind. In prokaryotes, gene expression requires a stretch of DNA called a promoter, which contains two motifs called –10 and –35 boxes. However, these motifs may occur in both promoters and non-promoter DNA in multiple copies. They have been implicated in some studies to improve promoter activity, and in others to repress it. Here, we ask whether the presence of such motifs in different genetic sequences influences promoter evolution and emergence. To understand whether and how promoter motifs influence promoter emergence and evolution, we start from 50 ‘promoter islands’, DNA sequences enriched with –10 and –35 boxes. We mutagenize these starting ‘parent’ sequences, and measure gene expression driven by 240,000 of the resulting mutants. We find that the probability that mutations create an active promoter varies more than 200-fold, and is not correlated with the number of promoter motifs. For parent sequences without promoter activity, mutations created over 1500 new –10 and –35 boxes at unique positions in the library, but only ~0.3% of these resulted in de-novo promoter activity. Only ~13% of all –10 and –35 boxes contribute to de-novo promoter activity. For parent sequences with promoter activity, mutations created new –10 and –35 boxes in 11 specific positions that partially overlap with preexisting ones to modulate expression. We also find that –10 and –35 boxes do not repress promoter activity. Overall, our work demonstrates how promoter motifs influence promoter emergence and evolution. It has implications for predicting and understanding regulatory evolution, de novo genes, and phenotypic evolution.
