Plant Homeo Domain Finger Protein 8 Regulates Mesodermal and Cardiac Differentiation of Embryonic Stem Cells Through Mediating the Histone Demethylation of pmaip1

Yan Tang, Ya Zhen Hong, Hua Jun Bai, Qiang Wu, Charlie Degui Chen, Jing Yu Lang, Kenneth R. Boheler, Huang Tian Yang

Research output: Contribution to journalArticlepeer-review

Abstract

Histone demethylases have emerged as key regulators of biological processes. The H3K9me2 demethylase plant homeo domain finger protein 8(PHF8), for example, is involved in neuronal differentiation, but its potential function in the differentiation of embryonic stem cells (ESCs) to cardiomyocytes is poorly understood. Here, we explored the role of PHF8 during mesodermal and cardiac lineage commitment of mouse ESCs (mESCs). Using a phf8 knockout (ph8-/Y) model, we found that deletion of phf8 in ESCs did not affect self-renewal, proliferation or early ectodermal/endodermal differentiation, but it did promote the mesodermal lineage commitment with the enhanced cardiomyocyte differentiation. The effects were accompanied by a reduction in apoptosis through a caspase 3-independent pathway during early ESC differentiation, without significant differences between differentiating wide-type (ph8+/Y) and ph8-/Y ESCs in cell cycle progression or proliferation. Functionally, PHF8 promoted the loss of a repressive mark H3K9me2 from the transcription start site of a proapoptotic gene pmaip1 and activated its transcription. Furthermore, knockdown of pmaip1 mimicked the phenotype of ph8-/Y by showing the decreased apoptosis during early differentiation of ESCs and promoted mesodermal and cardiac commitment, while overexpression of pmaip1 or phf8 rescued the phenotype of ph8-/Y ESCs by increasing the apoptosis and weakening the mesodermal and cardiac differentiation. These results reveal that the histone demethylase PHF8 regulates mesodermal lineage and cell fate decisions in differentiating mESCs through epigenetic control of the gene critical to programmed cell death pathways. A proposed model for the regulation of plant homeo domain finger protein 8 (PHF8) in ESC apoptosis and lineage commitment. Mechanistically, PHF8 promotes the loss of a repressive mark H3K9me2 from the transcription start site of a pro-apoptotic gene pmaip1 and activates its transcription, which leads to augmented mesodermal lineage specification and cardiac cell commitment but not to the early ectodermal or endodermal differentiation.

Original languageEnglish (US)
Pages (from-to)1527-1540
Number of pages14
JournalStem Cells
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

Keywords

  • Apoptosis
  • Embryonic stem cells
  • Histone demethylas
  • Mesodermal and cardiac differentiation
  • Phorbol-12-myristate-13-acetate-induced protein 1
  • Plant homeo domain finger protein 8

ASJC Scopus subject areas

  • General Medicine

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