The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

Abuhatzira, Liron; Shamir, Alon; Schones, Dustin E.; Schäffer, Alejandro A.; Bustin, Michael

doi:10.1074/jbc.m111.300541

Cited by 43 publications

(49 citation statements)

References 68 publications

(74 reference statements)

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“…The gene coding for HMGN1 is located in the Down syndrome critical region (46); HMGN1 protein is overexpressed in patients suffering from this syndrome, and mice with altered HMGN1 expression display behavioral abnormalities (19). Several of the HMGN1 targets identified here are consistent with these phenotypes.…”

Section: Hmgn Variants Fine Tune the Fidelity Of The Cellular Transcrsupporting

confidence: 58%

“…However, the presence of all HMGN variants in most tissues, and the phenotypes seen in Hmgn tm1/tm1 mice, argues for functional specificity. Thus, Hmgn1 tm1/tm1 mice exhibit behavioral abnormalities (19) and impaired repair of damaged DNA (20,21), whereas Hmgn3 tm1/tm1 mice are mildly diabetic (22 , and Hmgn5 tm1/tm1 mice and their wild type littermate controls to a battery of standardized tests designed to reveal abnormalities in several physiological properties (23,24). The various tests identified specific abnormalities in each of the mouse lines, reinforcing the general notion that HMGN variants are not fully redundant and raising the possibility that each variant has specific effects on the transcription profile of a tissue.…”

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confidence: 99%

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High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner

Kugler

Horsch

Huang

et al. 2013

Journal of Biological Chemistry

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The nuclei of most vertebrate cells contain members of the high mobility group N (HMGN) protein family, which bind specifically to nucleosome core particles and affect chromatin structure and function, including transcription. Here, we study the biological role of this protein family by systematic analysis of phenotypes and tissue transcription profiles in mice lacking functional HMGN variants. Phenotypic analysis of Hmgn1tm1/tm1, Hmgn3tm1/tm1, and Hmgn5tm1/tm1 mice and their wild type littermates with a battery of standardized tests uncovered variant-specific abnormalities. Gene expression analysis of four different tissues in each of the Hmgntm1/tm1 lines reveals very little overlap between genes affected by specific variants in different tissues. Pathway analysis reveals that loss of an HMGN variant subtly affects expression of numerous genes in specific biological processes. We conclude that within the biological framework of an entire organism, HMGNs modulate the fidelity of the cellular transcriptional profile in a tissue- and HMGN variant-specific manner.

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Section: Hmgn Variants Fine Tune the Fidelity Of The Cellular Transcrsupporting

confidence: 58%

mentioning

confidence: 99%

High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner

Kugler

Horsch

Huang

et al. 2013

Journal of Biological Chemistry

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“…The binding of HMGN1 induces chromatin structural changes at the binding sites within the promoter. HMGN1 binding reduced the enrichment of active histone mark H3K9Ac, while increasing the enrichment of H3K9me2, an inactive histone mark (Abuhatzira et al 2011). Chromatin immunoprecipitation results shown in ENCODE demonstrate unique distribution of histone PTMs throughout the MECP2/Mecp2 gene.…”

Section: Histone Posttranslational Modificationsmentioning

confidence: 96%

Rett Syndrome and MeCP2

2014

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Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

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“…HMGN1 affects chromatin structure and has been shown to down-regulate MECP2 [122]. In this study, alterations in HMGN1 levels have shown to alter chromatin structure and histone modifications in the MeCP2 promoter region.…”

Section: Mecp2 Duplication Syndromementioning

confidence: 80%

Epigenetics, Autism Spectrum, and Neurodevelopmental Disorders

2013

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Epigenetic marks are modifications of DNA and histones. They are considered to be permanent within a single cell during development, and are heritable across cell division. Programming of neurons through epigenetic mechanisms is believed to be critical in neural development. Disruption or alteration in this process causes an array of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Recent studies have provided evidence for an altered epigenetic landscape in ASDs and demonstrated the central role of epigenetic mechanisms in their pathogenesis. Many of the genes linked to the ASDs encode proteins that are involved in transcriptional regulation and chromatin remodeling. In this review we highlight selected neurodevelopmental disorders in which epigenetic dysregulation plays an important role. These include Rett syndrome, fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, and Kabuki syndrome. For each of these disorders, we discuss how advances in our understanding of epigenetic mechanisms may lead to novel therapeutic approaches.

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The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

Cited by 43 publications

References 68 publications

High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner

High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner

Rett Syndrome and MeCP2

Epigenetics, Autism Spectrum, and Neurodevelopmental Disorders

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