Project description:Yin Yang 1 (YY1) is a multifunctional transcription factor shown to be critical in a variety of biological processes. Although it has been reported to be regulated by multiple types of post-translational modifications (PTMs), whether YY1 is methylated, which enzyme methylates YY1, and hence the functional significance of YY1 methylation remain completely unknown. Here we reported the first methyltransferase, SET7/9 (KMT7), capable of methylating YY1 in vitro and in vivo at two highly conserved lysine (K) residues, K173 and K411, located in two distinct domains, one in the central glycine-rich region and the other in the very carboxyl-terminus. Functional study revealed that SET7/9-mediated YY1 methylation regulated YY1 DNA-binding activity both in vitro and at specific genomic loci in cultured cells. Consistently, SET7/9-mediated YY1 methylation was shown to involve in YY1-regulated gene transcription and cell proliferation. Our findings revealed a novel regulatory strategy, methylation by lysine methyltransferase, imposed on YY1 protein, and linked YY1 methylation with its biological functions.
Project description:Yin Yang 1 (YY1) is a multifunctional transcription factor shown to be critical in a variety of biological processes. Although it has been reported to be regulated by multiple types of post-translational modifications (PTMs), whether YY1 is methylated, which enzyme methylates YY1, and hence the functional significance of YY1 methylation remain completely unknown. Here we reported the first methyltransferase, SET7/9 (KMT7), capable of methylating YY1 in vitro and in vivo at two highly conserved lysine (K) residues, K173 and K411, located in two distinct domains, one in the central glycine-rich region and the other in the very carboxyl-terminus. Functional study revealed that SET7/9-mediated YY1 methylation regulated YY1 DNA-binding activity both in vitro and at specific genomic loci in cultured cells. Consistently, SET7/9-mediated YY1 methylation was shown to involve in YY1-regulated gene transcription and cell proliferation. Our findings revealed a novel regulatory strategy, methylation by lysine methyltransferase, imposed on YY1 protein, and linked YY1 methylation with its biological functions.
Project description:Yin Yang 1 (YY1) is a multifunctional transcription factor shown to be critical in a variety of biological processes. Although it is regulated by multiple types of post-translational modifications (PTMs), whether YY1 is methylated, which enzyme methylates YY1, and hence the functional significance of YY1 methylation remains completely unknown. Here we reported the first methyltransferase, SET7/9 (KMT7), capable of methylating YY1 at two highly conserved lysine (K) residues, K173 and K411, located in two distinct domains, one in the central glycine-rich region and the other in the very carboxyl-terminus. Functional studies revealed that SET7/9-mediated YY1 methylation regulated YY1 DNA-binding activity both in vitro and at specific genomic loci in cultured cells. Consistently, SET7/9-mediated YY1 methylation was shown to involve in YY1-regulated gene transcription and cell proliferation. Our findings revealed a novel regulatory strategy, methylation by lysine methyltransferase, imposed on YY1 protein, and linked YY1 methylation with its biological functions.
Project description:The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggest that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr-set7/SETD8 in the central nervous system is not well established. Here, we show that Drosophila Pr-Set7 is a novel regulator of NSC reactivation. Loss-of-function of pr-set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC-specific in vivo profiling, we demonstrate that Pr-set7 binds to the promoter region of cyclin dependent kinase 1 (cdk1) and Wnt pathway transcriptional co-activator earthbound1/jerky (ebd1). Further validation indicates that Pr-set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr-set7, Cdk1 and Ebd1 promote NSC reactivation. Moreover, Cdk1 upregulates the Ebd1 levels in NSCs, while Ebd1 appears to downregulate Cdk1 expression, suggesting a negative feedback regulation. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7-depleted brains. Therefore, Pr-set7, the sole H4K20 methyltransferase, promotes NSC reactivation through regulating Wnt signaling and cell-cycle progression. Given the conservation of Pr-set7, our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 in NSC proliferation and associated neurodevelopmental disorders.
Project description:Methyl-dependent regulation of transcription has expanded from a traditional focus on histones to encompass transcription factor modulation. While the Set7 lysine methyltransferase is associated with pro-inflammatory gene expression in vascular endothelial cells, genome-wide regulatory roles remain to be investigated. From initial characterization of Set7 as specific for methyl-lysine 4 of H3 histones (H3K4m1), biochemical activity toward non-histone substrates has revealed additional mechanisms of gene regulation. mRNA-Seq revealed transcriptional deregulation of over 8,000 genes in an endothelial model of Set7 knockdown. Gene ontology identified up-regulated pathways involved in developmental processes and extracellular matrix remodeling, whereas pathways regulating the inflammatory response as well as nitric oxide signaling were down-regulated. Chromatin maps derived from ChIP-Seq profiling of H3K4m1 identified several hundred loci with loss of H3K4m1 at gene regulatory elements associated with an unexpectedly subtle effect on gene expression. Transcription factor network analysis implicated six previously described Set7 substrates in mRNA-Seq changes, and we predict that Set7 post-translationally regulates other transcription factors associated with vascular endothelial gene expression through the presence of Set7 amino acid methylation motifs. We describe a role for Set7 in regulating developmental pathways and response to stimuli (inflammation/immune response) in human endothelial cells of vascular origin. Set7-dependent gene expression changes that occurred independent of H3K4m1 may involve transcription factor lysine methylation events. The method of mapping measured transcriptional changes to transcription factors to identify putative substrates with strong associations to functional changes is applicable to substrate prediction for other broad-substrate histone modifiers.
Project description:Investigate genes expression profiles of postmenopausal osteoporosis with kidney Yin deficiency in peripheral blood By TCM syndrome, 10 patients with postmenopausal osteoporosis were divided into three groups: kidney Yin deficiency (n=4), kidney Yang deficiency (n=3), non-kidney deficiency (n=3), another 3 healthy postmenopausal women also were selected as control group. Whole human genome oligo microarray were applied to explore gene expression difference of the groups. Kidney Yin deficiency group was compared with other three groups respectively.
Project description:Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain astrocyte identity in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.