Distinct dynamics and distribution of histone methyl-lysine derivatives in mouse development

Abstract

Histone methylation acts as an epigenetic regulator of chromatin activity through the modification of arginine and lysine residues on histones H3 and H4. In the case of lysine, this includes the formation of mono-, di-, or trimethyl groups, each of which is presumed to represent a distinct functional state at the cellular level. To examine the potential developmental roles of these modifications, we determined the global patterns of lysine methylation involving K9 on histone H3 and K20 on histone H4 in midgestation mouse embryos. For each lysine target site, we observed distinct subnuclear distributions of the mono- and trimethyl versions in 10T1/2 cells that were conserved within primary cultures and within the 3D-tissue architecture of the embryo. Interestingly, three of these modifications, histone H3 trimethyl K9, histone H4 monomethyl K20, and histone H4 trimethyl K20 exhibited marked differences in their distribution within the neuroepithelium. Specifically, both histone H3 trimethyl K9 and H4 monomethyl K20 were elevated in proliferating cells of the neural tube, which in the case of the K9 modification was limited to mitotic cells on the luminal surface. In contrast, histone H4 trimethyl K20 was progressively lost from these medial regions and became enriched in differentiating neurons in the ventrolateral neural tube. The inverse relationship of histone H4 K20 methyl derivatives is even more striking during skeletal and cardiac myogenesis where the accumulation of the trimethyl modification in pericentromeric heterochromatin suggests a role in gene silencing in postmitotic muscle cells. Importantly, our results establish that histone lysine methylation occurs in a highly dynamic manner that is consistent with their function in an epigenetic program for cell division and differentiation.

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

“…If we consider that differentiation starts with the loss of pluripotency but continues through development during further lineage specification, the mural trophectoderm presence might be indicative of a link between H4K20me3 and terminal differentiation of cell lineages during development. A previous study in midgestation mouse embryos suggested that H4K20me3 is associated with neural and muscle cell differentiation (Biron et al, 2004). In further support of a link with late differentiation are the regional differences we observed in the appearance of histone H4K20me3 trimethylation and HP1 protein: nuclear staining patterns in bone marrow remained more diffuse than in liver tissue and differentiated neural tissue, respectively (Fig.…”

“…Overall, based on the presence of H4K20me3 and HP1, our results suggest that these heterochromatin markers are acquired slowly during foetal development, first as a diffuse nuclear signal which subsequently concentrates into heterochromatic foci. Although a previous study (Biron et al, 2004) reported the presence of H4K20me3 in E8.5 and E11.5 localised brain structures, their results did not identify a clear nuclear pattern of this marker at the earlier stage. Nevertheless, foetal cell types may vary in heterochromatin maturation rates, as bone marrow tissue remained relatively unchanged between E14.5 and E17.5 embryos in contrast to brain tissue.…”

In situ histone landscape of nephrogenesis

“…Biron et al have shown that H3K9me3 is highly abundant in mitotic cells lining the medial edges and luminal aspects of the neural tube in E9.5 embryos, and suggested that this histone mark may be a useful and novel marker to define embryonic regions with high proliferative activity. 44 During folliculogenesis, primordial germ cells entrance into the genital ridge around E9.5-E11.5 is marked by accumulation of H3K9me3 and H3K27me3, whereas a more restricted peak in H3K4me3 occurs at E10.5. 45 This suggests that follicle maturation is marked by a period of poised chromatin domains containing active and repressive histone marks as part of a differentiation gene expression program.…”

Muscle‐specific expression of the smyd1 gene is controlled by its 5.3‐kb promoter and 5′‐flanking sequence in zebrafish embryos

“…Increasing evidence indicates that chromatin remodeling through histone modifications plays critical roles in gene expression and muscle cell differentiation (McKinsey et al, 2001Rupp et al, 2002;Zhang et al, 2002;Lee et al, 2004;Cirillo and Zaret, 2004;Biron et al, 2004). Histone acetylation often results in transcriptional activation.…”