Histone H3 lysine 4 methyltransferases and demethylases in self-renewal and differentiation of stem cells

Abstract

Epigenetic mechanisms are fundamental to understanding the regulatory networks of gene expression that govern stem cell maintenance and differentiation. Methylated histone H3 lysine 4 (H3K4) has emerged as a key epigenetic signal for gene transcription; it is dynamically modulated by several specific H3K4 methyltransferases and demethylases. Recent studies have described new epigenetic mechanisms by which H3K4 methylation modifiers control self-renewal and lineage commitments of stem cells. Such advances in stem cell biology would have a high impact on the research fields of cancer stem cell and regenerative medicine. In this review, we discuss the recent progress in understanding the roles of H3K4 methylation modifiers in regulating embryonic and adult stem cells' fates.

Figure 1

H3K4me3 marks actively transcribed and poised gene promoters in mammals. (A) The genome-wide correlation of mRNA expression levels (High, Medium, Low, and Silent) with H3K4me3 levels at human gene promoters. Note that a dip of H3K4me3 levels may be associated with the nucleosome-free region around the transcriptional start site (TSS). Adapted from [39]. (B) The Venn diagram showing the percentage of genes that have H3K4me3 and/or H3K27me3 in their promoters in mouse and human ES cells. All percentages are based on about total 18,000 genes. The “bivalent” denotes the promoters that contain both H3K4me3 and H3K27me3 marks. Adapted from [36,37,43].

Figure 2

Protein domain architectures and stem cell function of MLL/SET1 H3K4 methyltransferases. AT: AT-hook DNA binding domain; PHD: Plant Homeo Domain; BRD: Bromodomain; FYR: FY-rich domain; SET: Su(var)3-9, Enhancer of zeste, Trithorax domain; HMG: High Mobility Group domain; RRM: RNA Recognition Motif.

Figure 3

Protein domain architectures and stem cell function of other H3K4 methyltransferases and core subunits. AT: AT-hook DNA binding domain; AWS: Associated With SET domain; SET: Su(var)3-9, Enhancer of zeste, Trithorax domain; BRD: Bromodomain; PHD: Plant Homeo Domain; BAH: Bromo Adjacent Homology domain; MYND: Myeloid, Nervy, and DEAF-1 domain; MT: Mariner Transposase domain; KRAB: Krüppel Associated Box domain; C₂H₂: C₂H₂-type zinc finger; WD: WD40 repeat; SPRY: SplA and Ryanodine domain.

Figure 4

Protein domain architectures and stem cell function of H3K4 demethylases. SWIRM: SWI3, RSC8 and MOIRA domain; AOD-N: Amine Oxidase Domain-N terminal; TOWER: LSD1 tower domain; AOD-C: Amine Oxidase Domain-C terminal; C₄H₂C₂: C₄H₂C₂-type zinc finger; ZF_CW: CW-type zinc finger; AOD: Amine Oxidase Domain; JmjN: Jumonji N domain; ARID: AT-rich interactive domain; PHD: Plant Homeo Domain; JmjC: Jumonji C domain; C₅HC₂: C₅HC₂-type zinc finger.