HTZ-1/H2A.z and MYS-1/MYST HAT act redundantly to maintain cell fates in somatic gonadal cells through repression of ceh-22 in C. elegans

Abstract

The stable maintenance of acquired cell fates is important during development and for maintaining tissue homeostasis. Although histone modification is one of the major strategies used by cells to maintain their fates, the mechanisms by which histone variants maintain cell fates are not well understood. In C. elegans, the acetylated-histone-H4 (AcH4)-binding protein BET-1 acts downstream of the MYST family histone acetyltransferases MYS-1 and MYS-2 to establish and maintain cell fates in multiple cell lineages. Here we show that, in the bet-1 pathway, the histone H2A variant HTZ-1/H2A.z and MYS-1 are required for the maintenance of cell fates in a redundant manner. BET-1 controlled the subnuclear localization of HTZ-1. HTZ-1 and MYS-1 maintained the fates of the somatic gonadal cells (SGCs) through the repression of a target, ceh-22/Nkx2.5, which induced the formation of the leader cells of the gonad. H3K27 demethylase, UTX-1, had an antagonistic effect relative to HTZ-1 in the regulation of ceh-22. Nuclear spot assay revealed that HTZ-1 localized to the ceh-22 locus in SGCs in an utx-1-dependent manner. We propose that HTZ-1 and MYS-1 repress ceh-22 when UTX-1 removes its silencing mark, H3K27 methylation on the ceh-22 locus, thereby maintaining the fates of SGCs.

Maintenance of cell fates through acetylated histone and the histone variant H2A.z inC. elegans

“…23 In C. elegans, htz-1/H2A.z functions in the same genetic pathway with bet-1 in the maintenance of cell fates. 20 The disruption of the SWR1 homolog SSL-1 causes the same phenotype that occurs in bet-1 mutants. Disruption of HTZ-1 in the mys-1 background also causes a defect in the maintenance of cell fates.…”

“…However, in bet-1 mutants, ectopic expression of selector genes suggests that histone acetylation represses transcription through the activation of a BET-1-containing complex (see below). 20 Interestingly, genome-wide analyses in yeast suggest that each acetylation site appears to have a distinct role in transcriptional regulation, including transcriptional repression. 21 The mammalian BET family protein Brd4 is involved in repression of HPV (human papillomavirus) chromatin transcription.…”

“…14 Our results also suggests that BET-1 represses the transcription of ceh-22. 20 In addition, suppression of bet-1 phenotypes by RNAi of utx-1 that encodes H3K27 demethylase suggests that BET-1 and H3K27me has a similar effect in the maintenance of cell fates. 20 In addition, expression of egl-15 and sur-7 is upregulated in bet-1 mutants.…”

“…20 In addition, suppression of bet-1 phenotypes by RNAi of utx-1 that encodes H3K27 demethylase suggests that BET-1 and H3K27me has a similar effect in the maintenance of cell fates. 20 In addition, expression of egl-15 and sur-7 is upregulated in bet-1 mutants. 22 Thus, growing evidence indicates that histone acetylation also acts in transcriptional repression.…”

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

“…For example, H2A.Z has been shown to be required for the differentiation of ESCs as well as other cell types [64, 65•, 66]. H2A.Z is also critical for the development of various organisms including mice, Xenopus, Tetrahymena, Drosophila, and Caenorhabditis elegans [8], and it is responsible for the maintenance of cell fate in C. elegans [67]. The mechanistic details of how H2A.Z regulates repression of developmental genes in ESCs and their subsequent activation upon differentiation are still unclear.…”