Histone variant H2A.Z is required for early mammalian development

Abstract

Fundamental to the process of mammalian development is the timed and coordinated regulation of gene expression. This requires transcription of a precise subset of the total complement of genes. It is clear that chromatin architecture plays a fundamental role in this process by either facilitating or restricting transcription factor binding [1]. How such specialized chromatin structures are established to regulate gene expression is poorly understood. All eukaryotic organisms contain specialized histone variants with distinctly different amino acid sequences that are even more conserved than the major core histones [2]. On the basis of their highly conserved sequence, histone variants have been assumed critical for the function of mammalian chromatin; however, a requirement for a histone variant has not been shown in mammalian cells. Mice with a deletion of H1 degrees have been generated by gene targeting in ES cells, but these mice show no phenotypic consequences, perhaps due to redundancy of function [3]. Here we show for the first time that a mammalian histone variant, H2A.Z, plays a critical role in early development, and we conclude that this histone variant plays a pivotal role in establishing the chromatin structures required for the complex patterns of gene expression essential for normal mammalian development.

Reconciling the positive and negative roles of histone H2A.Z in gene transcription

“…46 Moreover in yeast, the deletion of either the Gal4 or Pho4 activators did not influence the ability of H2A.Z to be enriched at model target genes of these respective activators (Lemieux K and Gaudreau L, unpublished data). 47 Conversely, in human cells, results obtained by our and other laboratories suggest that targeting of H2A.Z, by virtue of the p400 or SRCAP such as Tetrahymena thermophila, 15 Xenopus laevis, 16,17 Drosophila melanogaster 18,19 and mice, 20 suggesting that it may provide distinct functions among different organisms. In budding yeast, loss of H2A.Z leads to defects in transcriptional activation, alterations in transcriptional silencing, and increased chromosome loss.…”

BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways

“…However, the molecular and developmental mechanisms controlling pluripotency and differentiation of ES cells are largely unknown, and only a very limited number of genes has so far been shown to affect the fate decisions of inner cell mass (ICM) or ES cells. These genes include Oct4, Fgf4, H2az, Foxd3, Nanog, and Sox2 (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Molecular cloning and polymorphism of the porcine H2AFZ gene

“…Our present study showed that there were some differences in NBA, but not in the TNB among genotypes, suggesting that pH2AFZ gene is related to fetal survival but not ovulation rate. Faast et al (2001) observed that heterozygous H2A.Z 1/2 mice appeared normal and were fertile, but none were homozygous for the H2A.Z mutation. This indicated that a lack of functional H2AFZ led to embryonic lethality.…”

“…H2AFZ gene has been characterized in the human (Hatch and Bonner, 1988, 1990and 1995, mouse (Faast et al, 2001), cow (Ball et al, 1983), rat (NM_022674) and other species. Mice deficient in H2AFZ died early in development, i.e., around the time of implantation (Faast et al, 2001).…”

“…H2AFZ gene has been characterized in the human (Hatch and Bonner, 1988, 1990and 1995, mouse (Faast et al, 2001), cow (Ball et al, 1983), rat (NM_022674) and other species. Mice deficient in H2AFZ died early in development, i.e., around the time of implantation (Faast et al, 2001). H2AFZ is localized to the transcription start sites of genes, and has both positive and negative regulatory functions in the gene expression process (Bruce et al, 2005;Guillemette et al, 2005;Kamakaka and Biggins, 2005;Raisner et al, 2005).…”