Project description:Lysine demethylase KDM7A removes histone modifications H3K9me1/2 and H3K27me1/2. KDM7A plays critical roles in gene expression and contribute to biological processes including tumorigenesis, metabolism, and embryonic development. However, the functions of KDM7A in mammalian nervous system are still poorly explored. In this study, functional roles of KDM7A are comprehensively investigated in neuronal cells by applying CUT&Tag-seq, RNA-seq and mice models. Knockdown of Kdm7a in N2A cells result in the alteration of histone modifications near transcription start sites (TSSs) and the expression changes of a large number of genes. In particular, the expression of immediate early genes (IEGs), a series of genes maintaining the function of the nervous system and associating with neurological disorders, are significantly decreased upon Kdm7a knockdown. Furthermore, in vivo knockdown of Kdm7a in dentate gyrus (DG) neuron of mice hippocampus, via Adeno-associated virus (AAV)-based stereotaxic microinjection, led to a significant decrease of the expression of c-Fos, a marker of neuron activity. Behavior assays in mice further revealed that Kdm7a knockdown in hippocampus repress neuron activity, which leading to impairment of emotion and memory. Collectively, the study reveals that KDM7A affects neuron functions by regulating IEGs, which may provide new clues for understanding epigenetic mechanisms in neurological disorders.
Project description:There are multiple post-translational modifications on amino acid residues at the N-terminus of histones that affect the structure of chromatin and alter the transcription of genes, thereby regulating a variety of biological processes. Lysine demethylase 7A (KDM7A) mainly removes histone modifications such as H3K9me1/2 and H3K27me1/2. Current research on KDM7A has focused on tumors, metabolism and development, while research on the function of the mammalian nervous system is still lacking. The functions and mechanisms of KDM7A in the regulation of neuronal cell differentiation and cell activity in the nervous system were investigated. Our study found that KDM7A regulates H3K9me2 and H3K27me2 but also affects other inhibitory or active histones, such as H3K9me3 and H3K27ac, thereby disturbing the transcription of some immediate early genes (IEGs) and consequently affecting the differentiation and activity of neuronal cells. IEGs are important for neuron cell proliferation, differentiation, formation of dendrites and neural circuit-related proteins, which are involved in maintaining the normal function of the nervous system. Imbalances in IEG expression have been found in some neurological disorders, such as depression and schizophrenia. Moreover, the changes in various histone modifications in neurodegenerative diseases and brain injury have recently received increasing attention. Therefore, our study provides a basis for revealing the epigenetic regulatory mechanisms of neurological disorders.
Project description:There are multiple post-translational modifications on amino acid residues at the N-terminus of histones that affect the structure of chromatin and alter the transcription of genes, thereby regulating a variety of biological processes. Lysine demethylase 7A (KDM7A) mainly removes histone modifications such as H3K9me1/2 and H3K27me1/2. Current research on KDM7A has focused on tumors, metabolism and development, while research on the function of the mammalian nervous system is still lacking. The functions and mechanisms of KDM7A in the regulation of neuronal cell differentiation and cell activity in the nervous system were investigated. Our study found that KDM7A regulates H3K9me2 and H3K27me2 but also affects other inhibitory or active histones, such as H3K9me3 and H3K27ac, thereby disturbing the transcription of some immediate early genes (IEGs) and consequently affecting the differentiation and activity of neuronal cells. IEGs are important for neuron cell proliferation, differentiation, formation of dendrites and neural circuit-related proteins, which are involved in maintaining the normal function of the nervous system. Imbalances in IEG expression have been found in some neurological disorders, such as depression and schizophrenia. Moreover, the changes in various histone modifications in neurodegenerative diseases and brain injury have recently received increasing attention. Therefore, our study provides a basis for revealing the epigenetic regulatory mechanisms of neurological disorders.
Project description:There are multiple post-translational modifications on amino acid residues at the N-terminus of histones that affect the structure of chromatin and alter the transcription of genes, thereby regulating a variety of biological processes. Lysine demethylase 7A (KDM7A) mainly removes histone modifications such as H3K9me1/2 and H3K27me1/2. Current research on KDM7A has focused on tumors, metabolism and development, while research on the function of the mammalian nervous system is still lacking. The functions and mechanisms of KDM7A in the regulation of neuronal cell differentiation and cell activity in the nervous system were investigated. Our study found that KDM7A regulates H3K9me2 and H3K27me2 but also affects other inhibitory or active histones, such as H3K9me3 and H3K27ac, thereby disturbing the transcription of some immediate early genes (IEGs) and consequently affecting the differentiation and activity of neuronal cells. IEGs are important for neuron cell proliferation, differentiation, formation of dendrites and neural circuit-related proteins, which are involved in maintaining the normal function of the nervous system. Imbalances in IEG expression have been found in some neurological disorders, such as depression and schizophrenia. Moreover, the changes in various histone modifications in neurodegenerative diseases and brain injury have recently received increasing attention. Therefore, our study provides a basis for revealing the epigenetic regulatory mechanisms of neurological disorders.
Project description:There are multiple post-translational modifications on amino acid residues at the N-terminus of histones that affect the structure of chromatin and alter the transcription of genes, thereby regulating a variety of biological processes. Lysine demethylase 7A (KDM7A) mainly removes histone modifications such as H3K9me1/2 and H3K27me1/2. Current research on KDM7A has focused on tumors, metabolism and development, while research on the function of the mammalian nervous system is still lacking. The functions and mechanisms of KDM7A in the regulation of neuronal cell differentiation and cell activity in the nervous system were investigated. Our study found that KDM7A regulates H3K9me2 and H3K27me2 but also affects other inhibitory or active histones, such as H3K9me3 and H3K27ac, thereby disturbing the transcription of some immediate early genes (IEGs) and consequently affecting the differentiation and activity of neuronal cells. IEGs are important for neuron cell proliferation, differentiation, formation of dendrites and neural circuit-related proteins, which are involved in maintaining the normal function of the nervous system. Imbalances in IEG expression have been found in some neurological disorders, such as depression and schizophrenia. Moreover, the changes in various histone modifications in neurodegenerative diseases and brain injury have recently received increasing attention. Therefore, our study provides a basis for revealing the epigenetic regulatory mechanisms of neurological disorders.
Project description:Temporal and spatial colinear expression of Hox genes determines the specification of positional identities of the embryo. Post-translational modifications of histones contribute to transcriptional regulation, and are required for proper control of biological processes, including differentiation and development. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 di-methylation of histone H3 (H3K9me2) and participates in transcriptional activation of developmental genes. However, the role of Kdm7a during mouse embryonic development remains to be elucidated. Here, we show that Kdm7a-/- mice exhibit anterior homeotic transformation of the axial skeleton (i.e. an increase in the number of presacral elements). Importantly, posterior Hox genes (caudally from Hox9) are specifically down-regulated in Kdm7a-/- embryos, which correlate with increased levels of H3K9me2. Taken together, these data suggest that Kdm7a is able to control transcription of posterior Hox genes, likely through its demethylating activity, and thereby regulating anterior-posterior development in mice.