The histone deacetylases HDAC1 and HDAC2 remove acetyl moieties from lysine residues of histones and other proteins and are important regulators of gene expression. By deleting different combinations of Hdac1 and Hdac2 alleles in the epidermis, we reveal a dosage-dependent effect of HDAC1/HDAC2 activity on epidermal proliferation and differentiation. Conditional ablation of either HDAC1 or HDAC2 in the epidermis leads to no obvious phenotype due to compensation by the upregulated paralogue. Strikingly, deletion of a single Hdac2 allele in HDAC1 knockout mice results in severe epidermal defects, including alopecia, hyperkeratosis, hyperproliferation and spontaneous tumour formation. These mice display impaired Sin3A co-repressor complex function, increased levels of c-Myc protein, p53 expression and apoptosis in hair follicles (HFs) and misregulation of HF bulge stem cells. Surprisingly, ablation of HDAC1 but not HDAC2 in a skin tumour model leads to accelerated tumour development. Our data reveal a crucial function of HDAC1/HDAC2 in the control of lineage specificity and a novel role of HDAC1 as a tumour suppressor in the epidermis.

One of the earliest organizational decisions in the development of the vertebrate brain is the division of the neural plate into Otx2-positive anterior and Gbx2-positive posterior territories. At the junction of these two expression domains, a local signaling center is formed, known as the midbrain-hindbrain boundary (MHB). This tissue coordinates or "organizes" the development of neighboring brain structures, such as the midbrain and cerebellum. Correct positioning of the MHB is thought to depend on mutual repression involving these two homeobox genes. Using a cell culture colocalization assay and coimmunoprecipitation experiments, we show that engrailed homology region 1 (eh1)-like motifs of both transcription factors physically interact with the WD40 domain of Groucho/Tle corepressor proteins. In addition, heat shock-induced expression of wild-type and mutant Otx2 and Gbx2 in medaka embryos demonstrates that Groucho is required for the repression of Otx2 by Gbx2. On the other hand, the repressive functions of Otx2 on Gbx2 do not appear to be dependent on corepressor interaction. Interestingly, the association of Groucho with Otx2 is also required for the repression of Fgf8 in the MHB. Therefore Groucho/Tle family members appear to regulate key aspects in the MHB development of the vertebrate brain.Gbx2 is a member of the homeobox gene family and has been identified in mammalian, avian, amphibian, and fish species (12,24,36,56,66). Gbx genes are related to the Drosophila unplugged gene, which is involved in tracheal branching (18). Gbx2 is a key player in the early patterning of the vertebrate brain and is expressed in the local signaling center known as the midbrain-hindbrain boundary (MHB) or isthmic organizer, which is positioned between the presumptive midbrain and hindbrain (reviewed in references 34, 54, 59, and 70). The Gbx2 expression domain is located at the region of the hindbrain, while the homeobox gene Otx2 is expressed in the presumptive forebrain and midbrain and thereby forms a common border with the Gbx2 domain at the position of the prospective MHB. Gbx2 mutant mice lack the anterior hindbrain and reveal a posterior expansion of the midbrain (67). In contrast, the anterior brain rostral to rhombomere 3 is deleted in Otx2-null mutant mice (3, 44). Misexpression of Gbx2 represses Otx2 expression in the posterior midbrain (46, 66), whereas misexpression of Otx2 in the anterior hindbrain represses Gbx2 expression in this region (11,35). Studies in Xenopus suggest that Otx and Gbx proteins needed for the positioning process function primarily as repressors rather than activators (28).Tle4 is one of the four full-length Groucho proteins in mammals (39, 63). The founding member of this conserved corepressor family is the Groucho gene of Drosophila. Groucho is known to play important roles in various developmental processes, including sex determination, segmentation, neurogenesis and dorsoventral patterning (22,50). Groucho family members are characterized by a conserved N-terminal glutamine-rich reg...

Histone deacetylases (HDACs) are a family of enzymes which regulate the acetylation state of nucleosomal histones, as well as non-histone proteins. By altering local chromatin architecture, HDACs play important roles in shaping cell differentiation and morphogenesis. Expression of class I HDACs during early chick development has so far not been analyzed. Here, we report the expression profile of chick class I HDACs from the onset of gastrulation (HH2) to day 4 of development and compare it to relevant stages during mouse development. Visualized by in situ hybridization to whole mount embryos and tissue sections, we found tissue-specific overlapping temporal and spatial expression domains for all four class I HDACs in chick and mouse, although species-specific differences could be identified. All class I HDACs in both species are highly expressed in the developing brain. In particular, HDAC1 is expressed at sites of anterior and posterior neural tube closure most obvious in the hot spot-like expression of HDAC1 in HH12 chicken embryos. A significant species-specific spatio-temporal expression pattern was observed for HDAC8. Whereas HDAC8 is exclusively found in fore-and midbrain regions during early mouse embryogenesis, the chick ortholog shows an expanded expression pattern, suggesting a more diversified role of HDAC8 in the chick system. Our results present a basis for further functional analysis of class I HDACs in chick development. KEY WORDS: histone deacetylase, chromatin, development, chick, mouseTranscriptional regulation in eukaryotes occurs within a chromatin setting and is strongly influenced by the posttranslational modification (PTM) of histones, the building blocks of chromatin. PTMs, such as methylation, phosphorylation and acetylation largely influence the readout of gene expression and represent an interface for binding factors and chromatin modifying enzymes (Strahl and Allis, 2000). A "histone code" has been suggested for the combination of distinct histone modifications that dramatically escalates the functional plasticity of the genome beyond the onedimensional nature of the primary DNA sequence (Jenuwein and Allis, 2001). Reversible histone acetylation is a dynamic process controlled by the antagonistic actions of two large families of enzymes -the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDACs remove acetyl moieties from histone tails, resulting in chromatin condensation and an overall reduction in transcriptional potential, while HAT activity results in local opening of chromatin thereby setting the stage for transcripInt. J. Dev. Biol. 54: 1527-1537 (2010) doi: 10.1387/ijdb.092971cm tion. By controlling dynamic acetylation patterns at specific chromatin regions, HATs and HDACs also modulate the affinity of acetyl-histone binding factors. The balance between the actions of these enzymes serves as a key regulatory mechanism for gene expression and plays important roles in the programming of multicellular development. Furthermore, it has been demons...

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