Histone H4K20me3 and HP1α are late heterochromatin markers in development, but present in undifferentiated embryonic stem cells

Wongtawan, Tuempong; Taylor, Jane; Lawson, Kirstie A.; Wilmut, Ian; Pennings, Sari

doi:10.1242/jcs.080721

Cited by 84 publications

(95 citation statements)

References 68 publications

(105 reference statements)

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“…Proper regulation of this process is crucial for embryo implantation and subsequent development. In recent years, several studies characterized histone modification patterns at the chromatin domains in preimplantation embryos as well as in mESCs and mTSCs (19,28,30,(52)(53)(54). However, prior to this study, the molecular mechanisms that regulate deposition of a histone mark at the chromatin domains of key TE regulators and their functional importance in TE lineage development had not been evaluated.…”

Section: Discussionmentioning

confidence: 99%

EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

Saha

Home²,

Ray³

et al. 2013

Molecular and Cellular Biology

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The first mammalian cell lineage commitment is the formation of the trophectoderm (TE) and the inner cell mass (ICM) lineages during preimplantation development. Proper development of the TE and ICM lineages is dependent upon establishment of specific transcriptional programs. However, the epigenetic mechanisms that functionally contribute to establish TE-and ICM-specific transcriptional programs are poorly understood. Here, we show that proper development of the TE and ICM lineages is coordinated via combinatorial regulation of embryonic ectoderm development (EED) and lysinespecific demethylase 6B (KDM6B). During blastocyst formation, the relative levels of EED and KDM6B expression determine altered polycomb repressor 2 (PRC2) complex recruitment and incorporation of the repressive histone H3 lysine 27 trimethylation (H3K27Me3) mark at the chromatin domains of TE-specific master regulators CDX2 and GATA3, leading to their activation in the TE lineage and repression in the ICM lineage. Furthermore, ectopic gain of EED along with depletion of KDM6B in preimplantation mouse embryos abrogates CDX2 and GATA3 expression in the nascent TE lineage. The loss of CDX2 and GATA3 in the nascent TE lineage results in improper TE development, leading to failure in embryo implantation to the uterus. Our study delineates a novel epigenetic mechanism that orchestrates proper development of the first mammalian cell lineages. Successful reproduction in placental mammals requires proper specification of the trophectoderm (TE) and the inner cell mass (ICM) lineages in preimplantation embryos. The ICM develops to the embryo proper, whereas the TE is essential for embryo implantation to the uterus and the origin of trophoblast cells of the placenta. During preimplantation mouse development, beginning at the 8-cell stage, blastomeres are polarized and allocated to inside and outside positions. During subsequent development, distinct transcriptional programs ensure the commitment of outside cells to the TE lineage and the inside cells to the ICM lineage (1-4). The TE is crucial for embryo implantation and develops into parts of the placenta. Improper TE specification results in either impaired preimplantation development or defective embryo implantation (5-8), which are the leading causes of infertility and early pregnancy failure.Several key transcription factors, like CDX2 and GATA3, have been implicated in proper development of the TE lineage (9-11). Gene-knockout studies in mice showed that another transcription factor, TEAD4, is essential for the establishment of the TE-specific transcriptional program and maturation of embryos to the blastocyst stage (12, 13). Interestingly, these key TE regulators have dynamic expression patterns during the course of preimplantation development. For example, transcription factors CDX2 and GATA3 are ubiquitously expressed in the blastomeres of an 8-cell mouse embryo. However, upon cell polarization, they are predominantly expressed in the outside cells (9,14). This pattern is maintained at the bla...

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Section: Discussionmentioning

confidence: 99%

EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

Saha

Home²,

Ray³

et al. 2013

Molecular and Cellular Biology

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“…1C). These modifications were paralleled by an increase in p21 wa61 and acidic b-galactosidase signals, underlying the onset of premature senescence in these cells (19). We previously reported that a designed epigenetic cocktail (EpiC) made of retinoid, phenylbutyrate, and a nitric oxide donor (11) induced a cardiac precursors-like phenotype in CMSC stimulating the expression of early cardiovascular markers.…”

Section: Isolated Nd-cmsc and D-cmsc Show Distinct Proliferation Ratesmentioning

confidence: 94%

The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

et al. 2014

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This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-a general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients.In recent decades, in association with the progressive increase of the average population age in western countries, type 2

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“…These marks may be resolved as development proceeds leading to developmental and tissue specific patterns of gene expression (Barski et al, 2007;Boyer et al, 2006). Mature heterochromatin HP1alpha and H4K20me3 signatures do not arise until late in development (Wongtawan et al, 2011). Like DNA methylation, gene silencing via histone modification can be maintained in vivo through multiple cell divisions.…”

Section: Histone Modifications and Gene Regulationmentioning

confidence: 99%

DNA Methylation in Mammalian and Non-Mammalian Organisms

Moffat¹,

Reddington²,

Pennings³

et al. 2012

DNA Methylation - From Genomics to Technology

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Histone H4K20me3 and HP1α are late heterochromatin markers in development, but present in undifferentiated embryonic stem cells

Cited by 84 publications

References 68 publications

EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

DNA Methylation in Mammalian and Non-Mammalian Organisms

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