RESUMO
Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of Tgm1, Krt16, and Aqp3 In parallel, HDAC3 suppresses expression of inflammatory cytokines through a Rela-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.
Assuntos
Diferenciação Celular/genética , Células Epidérmicas/citologia , Epiderme/embriologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Animais , Embrião de Mamíferos , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais/genética , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Correpressor 2 de Receptor Nuclear/genética , Correpressor 2 de Receptor Nuclear/metabolismo , Domínios e Motivos de Interação entre Proteínas/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismoRESUMO
The constitutive activation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has been demonstrated to be critical in clinical cancer patients as well as in laboratory cancer models including hematological malignancies. Great efforts have been made to develop inhibitors targeting this pathway in hematological malignancies but so far the efficacies of these inhibitors were not as good as expected. By analyzing existing literatures and datasets available, we found that mutations of genes in the pathway only constitute a very small subset of hematological malignancies. Deep understanding of the function of gene, the pathway and/or its regulators, and the cellular response to inhibitors, may help us design better drugs targeting the hematological malignancies.