Compensatory functions of histone deacetylase 1 (HDAC1) and HDAC2 regulate transcription and apoptosis during mouse oocyte development

Abstract

Dramatic changes in chromatin structure and histone modification occur during oocyte growth, as well as a global cessation of transcription. The role of histone modifications in these processes is poorly understood. We report the effect of conditionally deleting Hdac1 and Hdac2 on oocyte development. Deleting either gene has little or no effect on oocyte development, whereas deleting both genes results in follicle development arrest at the secondary follicle stage. This developmental arrest is accompanied by substantial perturbation of the transcriptome and a global reduction in transcription even though histone acetylation is markedly increased. There is no apparent change in histone repressive marks, but there is a pronounced decrease in histone H3K4 methylation, an activating mark. The decrease in H3K4 methylation is likely a result of increased expression of Kdm5b because RNAi-mediated targeting of Kdm5b in double-mutant oocytes results in an increase in H3K4 methylation. An increase in TRP53 acetylation also occurs in mutant oocytes and may contribute to the observed increased incidence of apoptosis. Taken together, these results suggest seminal roles of acetylation of histone and nonhistone proteins in oocyte development.O ogenesis is a protracted process that encompasses meiosis and oocyte growth, and results in the only cell that, following fertilization, can develop into an organism (1). In mice, at approximately day 13.5 of gestation, oogonia undergo a final round of DNA replication and enter the first meiotic prophase, at which point they are called oocytes. By the time of birth, oocytes are arrested in diplotene of the first meiotic prophase, are approximately 15 to 20 μm in diameter, and reside in primordial follicles in which the oocyte is surrounded by a single layer of flattened follicle cells. Oocyte growth is coordinated with follicle cell proliferation; the diameter of full-grown oocytes is approximately 80 μm. During the growth phase, oocytes acquire the ability to resume meiosis (i.e., acquisition of meiotic competence) and support development to term (i.e., acquisition of developmental competence). In vivo, release of gonadotropins triggers resumption of meiosis of full-grown oocytes present in preovulatory follicles with oocytes maturing to and arresting at metaphase II; fertilization triggers resumption and completion of meiosis (2).Oocyte growth is accompanied by dramatic changes in gene expression, but starting at approximately midgrowth phase, transcription decreases such that full-grown oocytes are essentially transcriptionally inactive (3), and transcriptional quiescence appears critical for acquisition of developmental competence (4). Transcriptional quiescence is associated with chromatin condensation as well as changes in histone posttranslational modifications (PTMs) (5); histone PTMs such as phosphorylation, methylation, ubiquitination, and acetylation are intimately linked to transcriptional regulation and required for many biological processes (6, 7), with histone acetylation ...

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

“…40,41 Detailed temporal and spatial patterns of HDAC1 and HDAC2 expression have been established by immunocytochemical analysis. 35,42,43 HDAC1 and HDAC2 are concentrated in the nucleus throughout oocyte growth. 43 The intensity of HDAC1 nuclear staining displays a progressive decrease during the course of oocyte growth and following resumption of meiosis (i.e., germinal vesicle breakdown (GVBD)) HDAC1 colocalizes with chromosomes.…”

“…35,42,43 HDAC1 and HDAC2 are concentrated in the nucleus throughout oocyte growth. 43 The intensity of HDAC1 nuclear staining displays a progressive decrease during the course of oocyte growth and following resumption of meiosis (i.e., germinal vesicle breakdown (GVBD)) HDAC1 colocalizes with chromosomes. In contrast, nuclear HDAC2 staining increases between days 5 and 12 post-partum and then remains relatively constant for the duration of the growth phase.…”

“…After GVBD, HDAC2 is uniformly dispersed throughout the cytoplasm. 42,43 Following fertilization, HDAC2 again appears in the pronucleus/nucleus, and the intensity of HDAC2 nuclear staining progressively decreases during preimplatation development. 42 HDAC1 staining, on the other hand, is largely confined to the cytoplasm in fertilized eggs and early 2-cell embryos with enrichment in the nucleus becoming visible in the late 2-cell embryo, concomitant with zygotic genome activation ( Figure 2).…”

“…9,16,28 Likewise, deletion of either Hdac1 or Hdac2 does not evoke an obvious effect on oocyte development to the full-grown oocyte stage. 43 Deletion of both Hdac1 and Hdac2, however, results in infertility due to oocyte development arresting at the secondary follicle stage, which is accompanied by mis-regulation of histone modifications, a significant reduction of global transcription, and an increased incidence of apoptosis. These results suggest an apparent compensatory function of HDAC1 and HDAC2 in oocytes.…”

“…43 Nevertheless, deletion of three of the four Hdac1/Hdac2 alleles shows that HDAC1 and HDAC2 function unequally during oocyte development. Haploinsufficency of Hdac1 in the absence of HDAC2 (Hdac1 − / + /Hdac2 −/− ) reveals a more important function of HDAC2 in oocytes, the mice are infertile, 43 whereas in the opposite allelic combination, a single Hdac2 allele in the absence of HDAC1 does not produce any apparent phenotypes. These results suggest that HDAC2 function is more critical for oocyte development than HDAC1.…”