Macrohistone Variants Preserve Cell Identity by Preventing the Gain of H3K4me2 during Reprogramming to Pluripotency

Barrero, María J.; Sesé, Borja; Kuebler, Bernd; Bilić, Josipa; Boué, Stéphanie; Martí, Mercè; Belmonte, Juan Carlos Izpisúa

doi:10.1016/j.celrep.2013.02.029

Cited by 76 publications

(108 citation statements)

References 34 publications

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“…While evidence for such a role has been detected for the inactive X chromosome (44,45), a cell-type-specific gene (19), and the induction of pluripotency (43,46,47), our study of macroH2A double KO liver did not detect obvious derepression of genes that should be silent in the liver. Our studies of whole tissues cannot rule out the derepression of silent genes in a small percentage of cells or widespread derepression resulting in a very low level of expression.…”

Section: Discussionmentioning

confidence: 61%

Mice without MacroH2A Histone Variants

Pehrson

Changolkar

Costanzi

et al. 2014

Molecular and Cellular Biology

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MacroH2A core histone variants have a unique structure that includes a C-terminal nonhistone domain. They are highly conserved in vertebrates and are thought to regulate gene expression. However, the nature of genes regulated by macroH2As and their biological significance remain unclear. Here, we examine macroH2A function in vivo by knocking out both macroH2A1 and macroH2A2 in the mouse. While macroH2As are not required for early development, the absence of macroH2As impairs prenatal and postnatal growth and can significantly reduce reproductive efficiency. The distributions of macroH2A.1-and macroH2A.2-containing nucleosomes show substantial overlap, as do their effects on gene expression. Our studies in fetal and adult liver indicate that macroH2As can exert large positive or negative effects on gene expression, with macroH2A.1 and macroH2A.2 acting synergistically on the expression of some genes and apparently having opposing effects on others. These effects are very specific and in the adult liver preferentially involve genes related to lipid metabolism, including the leptin receptor. MacroH2A-dependent gene regulation changes substantially in postnatal development and can be strongly affected by fasting. We propose that macroH2As produce adaptive changes to gene expression, which in the liver focus on metabolism. MacroH2A core histone variants have a unique structure in which an N-terminal H2A domain is connected to a C-terminal nonhistone domain (1). The H2A domain can substitute for conventional H2A in the nucleosome, and we estimated that ϳ1 in 30 nucleosomes contains a macroH2A in adult rat liver (1, 2), an organ with relatively high macroH2A content. Most of the nonhistone region consists of an evolutionarily conserved domain (3) called a macrodomain. Macrodomains are found in a variety of proteins and as stand-alone proteins in many bacteria (3, 4). Some, but not all, macrodomains bind ADP-ribose with high affinity (5, 6).MacroH2As show a complex distribution in metazoan organisms (7). The basal metazoan species Trichoplax adhaerens and the sponge Amphimedon queenslandica have a macroH2A gene, as does Hydra magnipapillata, clearly indicating its presence in early metazoan evolution. While some other invertebrate genomes contain a macroH2A gene, many complete or nearly complete invertebrate genomes lack macroH2A: e.g., macroH2A is present in a sea urchin (Strongylocentrotus purpuratus), a tick (Ixodes scapularis), and an annelid (Capitella teleta) but is absent in sequenced insects, a nematode (Caenorhabditis elegans), and a tunicate (Ciona intestinalis). Two highly conserved macroH2A genes, macroH2A1 and macroH2A2, are found in mammalian genomes, and clearly homologous genes can be found in birds, reptiles, and fish. To our knowledge, macroH2A genes have not been detected in fungal, protozoan, or plant genomes. These findings indicate that macroH2As first appeared in early metazoan evolution and were lost in some invertebrate lineages but were strongly retained in higher vertebrate species.In mice, hu...

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Section: Discussionmentioning

confidence: 61%

Mice without MacroH2A Histone Variants

Pehrson

Changolkar

Costanzi

et al. 2014

Molecular and Cellular Biology

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“…The expression of the histone variant mH2A2 has been described to be high in terminally differentiated cells (Pehrson et al, 1997) and during adult stem cell differentiation (Barrero et al, 2013).…”

Section: Satellite Cells Undergo Terminal Differentiation Inside the mentioning

confidence: 99%

Mcad-mediated intercellular interactions activate satellite cell division

Martí

Montserrat

Pardo

et al. 2013

Journal of Cell Science

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SummaryAdult muscle stem cells and their committed myogenic precursors, commonly referred to as the satellite cell population, are involved in both muscle growth after birth and regeneration after damage. It has been previously proposed that, under these circumstances, satellite cells first become activated, divide and differentiate, and only later fuse to the existing myofiber through M-cadherin-mediated intercellular interactions. Our data show that satellite cells fuse with the myofiber concomitantly to cell division, and only when the nuclei of the daughter cells are inside the myofiber, do they complete the process of differentiation. Here we demonstrate that Mcadherin plays an important role in cell-to-cell recognition and fusion, and is crucial for cell division activation. Treatment of satellite cells with M-cadherin in vitro stimulates cell division, whereas addition of anti-M-cadherin antibodies reduces the cell division rate. Our results suggest an alternative model for the contribution of satellite cells to muscle development, which might be useful in understanding muscle regeneration, as well as muscle-related dystrophies.

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“…S3D). Dimethylated-H3me2K4 is one of the early marks associated with reprogramming, and enrichment of this mark at different loci is inhibited by the recruitment of the MacroH2A.1 variant (Barrero et al, 2013). We determined the incorporation of the H3me2K4 level within the pluripotency genes.…”

Section: Downregulation Of Aplf Favors Enrichment Of H3me2k4 Marks Atmentioning

confidence: 99%

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

Syed¹,

Joseph²,

Mukherjee³

et al. 2017

Development

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The authors apologise to the readers for any confusion that this error might have caused. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Downregulation of APLF in MEFs expedites the loss of the repressive MacroH2A.1 (encoded by H2afy) histone variant from the Cdh1 promoter and enhances the incorporation of active histone H3me2K4 marks at the promoters of the pluripotency genes Nanog and Klf4, thereby accelerating the process of cellular reprogramming and increasing the efficiency of iPSC generation. We demonstrate a new histone chaperone (APLF)-MET-histone modification cohort that functions in the induction of pluripotency in fibroblasts. This regulatory axis might provide new mechanistic insights into perspectives of epigenetic regulation involved in cancer metastasis.

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Macrohistone Variants Preserve Cell Identity by Preventing the Gain of H3K4me2 during Reprogramming to Pluripotency

Cited by 76 publications

References 34 publications

Mice without MacroH2A Histone Variants

Mice without MacroH2A Histone Variants

Mcad-mediated intercellular interactions activate satellite cell division

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

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