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      Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability

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          Abstract

          Intellectual disability (ID) affects up to 2% of the population world-wide and often coincides with other neurological conditions such as autism spectrum disorders. Mutations in KDM5C cause Mental Retardation, X-linked, Syndromic, Claes-Jensen type (MRXSCJ, OMIM #300534) and are one of the most common causes of X-linked ID. KDM5C encodes a histone demethylase for di- and tri-methylated histone H3 lysine 4 (H3K4me2/3), which are enriched in transcriptionally engaged promoter regions. KDM5C regulates gene transcription; however, it remains unknown whether removal of H3K4me is fully responsible for KDM5C-mediated gene regulation. Most mutations functionally tested to date result in reduced enzymatic activity of KDM5C, indicating loss of demethylase function as the primary mechanism underlying MRXSCJ. Here, we report a novel KDM5C mutation, R1115H, identified in an individual displaying MRXSCJ-like symptoms. The carrier mother’s cells exhibited a highly skewed X-inactivation pattern. The KDM5C-R1115H substitution does not have an impact on enzymatic activity nor protein stability. However, when overexpressed in post-mitotic neurons, KDM5C-R1115H failed to fully suppress expression of target genes, while the mutant also affected expression of a distinct set of genes compared to KDM5C-wildtype. These results suggest that KDM5C may have non-enzymatic roles in gene regulation, and alteration of these roles contributes to MRXSCJ in this patient.

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          Most cited references27

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          A high-resolution recombination map of the human genome.

          Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.
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            The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases.

            Histone methylation regulates chromatin structure and transcription. The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4me3). We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products. Other SMCX family members, including SMCY, RBP2, and PLU-1, also demethylated H3K4me3. SMCX bound H3K9me3 via its N-terminal PHD (plant homeodomain) finger, which may help coordinate H3K4 demethylation and H3K9 methylation in transcriptional repression. Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively. Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity. Our findings thus identify a family of H3K4me3 demethylases and uncover a critical link between histone modifications and XLMR.
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              An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells.

              The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. These findings show that pretreatment of cancer cells with a KDM5-specific inhibitor results in the ablation of a subpopulation of cancer cells that can serve as the founders for therapeutic relapse.
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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                04 April 2018
                2018
                : 11
                : 104
                Affiliations
                [1] 1Department of Human Genetics, University of Michigan , Ann Arbor, MI, United States
                [2] 2Diagnostic Laboratory, Greenwood Genetic Center , Greenwood, SC, United States
                [3] 3Molecular & Behavioral Neuroscience Institute, University of Michigan , Ann Arbor, MI, United States
                [4] 4Department of Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, MI, United States
                [5] 5Department of Psychiatry, University of Michigan , Ann Arbor, MI, United States
                [6] 6Division of Genetics, Department of Pediatrics, University of Michigan , Ann Arbor, MI, United States
                Author notes

                Edited by: Marta Biagioli, University of Trento, Italy

                Reviewed by: Yuri Bozzi, University of Trento, Italy; Corrado Romano, Associazione Oasi Maria SS. Onlus (IRCCS), Italy

                *Correspondence: Shigeki Iwase, siwase@ 123456umich.edu
                Article
                10.3389/fnmol.2018.00104
                5893713
                29670509
                63fe7bd8-b6f2-42ac-b771-35ad225fffce
                Copyright © 2018 Vallianatos, Farrehi, Friez, Burmeister, Keegan and Iwase.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 October 2017
                : 15 March 2018
                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 36, Pages: 12, Words: 0
                Funding
                Funded by: National Institute of General Medical Sciences 10.13039/100000057
                Award ID: T32-GM07544
                Funded by: National Institute of Child Health and Human Development 10.13039/100000071
                Award ID: T32-HD079342
                Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000071
                Award ID: R01NS089896
                Funded by: Autism Science Foundation 10.13039/100008152
                Funded by: Michigan Institute for Clinical and Health Research 10.13039/100008269
                Award ID: UL1TR000433
                Award ID: UL1TR002240
                Funded by: Horace H. Rackham School of Graduate Studies, University of Michigan 10.13039/100006801
                Funded by: March of Dimes Foundation 10.13039/100000912
                Categories
                Neuroscience
                Original Research

                Neurosciences
                autism spectrum disorders,x-linked intellectual disability,kdm5c/smcx/jarid1c,mutation analysis,chromatin,histone demethylase,neuroepigenetics

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