The histone variant macroH2A confers functional robustness to the intestinal stem cell compartment

Autor: Nicolae Adrian Leu, Ning Li, Maryam Yousefi, Ryan J. Cedeno, Christopher J. Lengner, Stephanie Sterling, John R. Pehrson, Angela Nakauka-Ddamba
Rok vydání: 2017
Předmět:
0301 basic medicine
Carcinogenesis
Physiology
lcsh:Medicine
medicine.disease_cause
Biochemistry
Epithelium
Histones
Gene Knockout Techniques
Mice
Intestinal mucosa
Medicine and Health Sciences
Homeostasis
Intestinal Mucosa
Organ Cultures
lcsh:Science
Staining
Regulation of gene expression
Multidisciplinary
Stem Cells
Specimen preparation and treatment
Intestinal epithelium
Cell biology
Intestines
Organoids
Nucleic acids
Oncology
Small Intestine
Biological Cultures
Anatomy
Stem cell
Research Article
DNA damage
Cell fate determination
Biology
Research and Analysis Methods
digestive system
03 medical and health sciences
Intestinal Neoplasms
Genetics
medicine
Animals
Humans
Regeneration
Epigenetics
lcsh:R
fungi
DAPI staining
Biology and Life Sciences
DNA
HCT116 Cells
Gastrointestinal Tract
Biological Tissue
030104 developmental biology
Gene Expression Regulation
Nuclear staining
Immunology
lcsh:Q
Physiological Processes
Digestive System
Zdroj: PLoS ONE
PLoS ONE, Vol 12, Iss 9, p e0185196 (2017)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0185196
Popis: A stem cell's epigenome directs cell fate during development, homeostasis, and regeneration. Epigenetic dysregulation can lead to inappropriate cell fate decisions, aberrant cell function, and even cancer. The histone variant macroH2A has been shown to influence gene expression, guide cell fate, and safeguard against genotoxic stress. Interestingly, mice lacking functional macroH2A histones (hereafter referred to as macroH2A DKO) are viable and fertile; yet suffer from increased perinatal death and reduced weight and size compared to wildtype (WT). Here, we ask whether the ostensible reduced vigor of macroH2A DKO mice extends to intestinal stem cell (ISC) function during homeostasis, regeneration, and oncogenesis. Lgr5-eGFP-IRES-CreERT2 or Hopx-CreERT2::Rosa26-LSL-tdTomato ISC reporter mice or the C57BL/6J-Apcmin/J murine intestinal adenoma model were bred into a macroH2A DKO or strain-matched WT background and assessed for ISC functionality, regeneration and tumorigenesis. High-dose (12Gy) whole-body γ-irradiation was used as an injury model. We show that macroH2A is dispensable for intestinal homeostasis and macroH2A DKO mice have similar numbers of active crypt-base columnar ISCs (CBCs). MacroH2A DKO intestine exhibits impaired regeneration following injury, despite having significantly more putative reserve ISCs. DKO reserve ISCs disproportionately undergo apoptosis compared to WT after DNA damage infliction. Interestingly, a macroH2A DKO background does not significantly increase tumorigenesis in the Apcmin model of intestinal adenoma. We conclude that macroH2A influences reserve ISC number and function during homeostasis and regeneration. These data suggest macroH2A enhances reserve ISC survival after DNA damage and thus confers functional robustness to the intestinal epithelium.
Databáze: OpenAIRE
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