RESUMO
Autophagy is a catabolic process through which cytoplasmic components are degraded and recycled in response to various stresses including starvation. Recently, transcriptional and epigenetic regulations of autophagy have emerged as essential mechanisms for maintaining homeostasis. Here, we identify that coactivator-associated arginine methyltransferase 1 (CARM1) methylates Pontin chromatin-remodeling factor under glucose starvation, and methylated Pontin binds Forkhead Box O 3a (FOXO3a). Genome-wide analyses and biochemical studies reveal that methylated Pontin functions as a platform for recruiting Tip60 histone acetyltransferase with increased H4 acetylation and subsequent activation of autophagy genes regulated by FOXO3a. Surprisingly, CARM1-Pontin-FOXO3a signaling axis can work in the distal regions and activate autophagy genes through enhancer activation. Together, our findings provide a signaling axis of CARM1-Pontin-FOXO3a and further expand the role of CARM1 in nuclear regulation of autophagy.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Autofagia/genética , DNA Helicases/metabolismo , Epigênese Genética , Proteína-Arginina N-Metiltransferases/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , Acetilação , Animais , Arginina/metabolismo , DNA Helicases/genética , Fibroblastos , Proteína Forkhead Box O3/metabolismo , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Glucose/metabolismo , Células HEK293 , Células HeLa , Células Hep G2 , Histonas/metabolismo , Humanos , Lisina Acetiltransferase 5/metabolismo , Metilação , Camundongos Transgênicos , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais/genética , Transativadores/metabolismo , Ativação TranscricionalRESUMO
Epigenetic regulation is important for establishing lineage-specific gene expression during early development. Although signaling pathways have been well-studied for regulation of trophectoderm reprogramming, epigenetic regulation of trophectodermal genes with histone modification dynamics have been poorly understood. Here, we identify that plant homeodomain finger protein 6 (PHF6) is a key epigenetic regulator for activation of trophectodermal genes using RNA-sequencing and ChIP assays. PHF6 acts as an E3 ubiquitin ligase for ubiquitination of H2BK120 (H2BK120ub) via its extended plant homeodomain 1 (PHD1), while the extended PHD2 of PHF6 recognizes acetylation of H2BK12 (H2BK12Ac). Intriguingly, the recognition of H2BK12Ac by PHF6 is important for exerting its E3 ubiquitin ligase activity for H2BK120ub. Together, our data provide evidence that PHF6 is crucial for epigenetic regulation of trophectodermal gene expression by linking H2BK12Ac to H2BK120ub modification.
