Differential expression of the HMGN family of chromatin proteins during ocular development

Lucey, Michelle; Wang, Yan; Bustin, Michael; Duncan, Melinda K.

doi:10.1016/j.gep.2008.04.002

Cited by 19 publications

(15 citation statements)

References 28 publications

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“…Thus, Hmgn1 −/− n2 −/− mice show changes in eye morphology that were not seen in mice lacking a single HMGN variant, most likely because both variants are strongly expressed in the eye (Lucey et al 2008). Thus, the phenotypic analyses indicate that loss of both HMGN1 and HMGN2 lead to more detectable phenotypes than loss of only HMGN1 or HMGN2, a finding that is in general agreement the compensatory binding of HMGN variants to chromatin and with the more severe changes in the DHS landscape of Hmgn1…”

Section: Wwwgenomeorgmentioning

confidence: 98%

Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

et al. 2015

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DNase I hypersensitive sites (DHSs) are a hallmark of chromatin regions containing regulatory DNA such as enhancers and promoters; however, the factors affecting the establishment and maintenance of these sites are not fully understood. We now show that HMGN1 and HMGN2, nucleosome-binding proteins that are ubiquitously expressed in vertebrate cells, maintain the DHS landscape of mouse embryonic fibroblasts (MEFs) synergistically. Loss of one of these HMGN variants led to a compensatory increase of binding of the remaining variant. Genome-wide mapping of the DHSs in Hmgn1 −/− , Hmgn2 −/− , and Hmgn1 −/− n2 −/− MEFs reveals that loss of both, but not a single HMGN variant, leads to significant remodeling of the DHS landscape, especially at enhancer regions marked by H3K4me1 and H3K27ac. Loss of HMGN variants affects the induced expression of stress-responsive genes in MEFs, the transcription profiles of several mouse tissues, and leads to altered phenotypes that are not seen in mice lacking only one variant. We conclude that the compensatory binding of HMGN variants to chromatin maintains the DHS landscape, and the transcription fidelity and is necessary to retain wildtype phenotypes. Our study provides insight into mechanisms that maintain regulatory sites in chromatin and into functional compensation among nucleosome binding architectural proteins. [Supplemental material is available for this article.]Tissue-and developmental-specific gene expression is facilitated by the binding of transcription factors to unique DNA sequences at regulatory sites in chromatin, such as enhancers and promoters. At these sites, the organization of the nucleosomes is altered, rendering the DNA more accessible to regulatory factors and hypersensitive to digestion by various nucleases including DNase I. DNase I hypersensitive sites (DHSs) are a hallmark of chromatin regions containing regulatory DNA and are used to identify regulatory sites in chromatin. The DHSs chromatin landscape is cell-type specific and dynamic, reflecting changes in the cellular transcription profile occurring during development, or as a consequence of genomic changes leading to altered cellular phenotypes (Gross and Garrard 1988;Boyle et al. 2008;Thurman et al. 2012;Calo and Wysocka 2013;Stergachis et al. 2013).The molecular mechanisms that establish and maintain DHSs and their role in gene expression are key questions in chromatin biology. DHSs are established by the combined action of transcription factors that bind dynamically to specific DNA sequences and 12 These authors contributed equally to this work.

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Section: Wwwgenomeorgmentioning

confidence: 98%

Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

et al. 2015

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“…HMGN proteins compete with other architectural proteins for chromatin binding sites and therefore can be viewed as functioning within a dynamic network of proteins that continuously move among nucleosomes, constantly reconfiguring their chromatin binding sites (8). The three members of this family, HMGN1, HMGN2, and HMGN3, have a highly conserved domain structure and very similar biochemical properties (6); however, their expression levels vary among tissues (26,40). …”

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The Nucleosome Binding Protein HMGN3 Modulates the Transcription Profile of Pancreatic β Cells and Affects Insulin Secretion

Ueda¹,

Furusawa²,

Kurahashi³

et al. 2009

Molecular and Cellular Biology

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Improper glucose-stimulated insulin secretion from pancreatic ␤ cells is a major factor in the onset of type 2 diabetes. We now report that HMGN3, a nuclear protein that binds to nucleosomes and affects chromatin function, is highly expressed in ␤ cells and that in mice, loss of HMGN3 impairs glucose-stimulated insulin secretion and leads to a diabetic phenotype. In pancreatic ␤ cells, loss of HMGN3 affects the transcription of several genes involved in glucose-stimulated insulin secretion, including that of the Glut2 glucose transporter. Chromatin immunoprecipitation reveals that HMGN3 and the transcription factor PDX1 mutually reinforce their specific binding to the chromatin in the promoter of the Glut2 gene, thereby regulating GLUT2 protein levels in pancreatic islets and in ␤ cells. Our results identify a new regulator of glucose homeostasis and demonstrate a link between the activity of a nucleosome binding structural protein and the regulation of insulin secretion.

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“…HMGN3a and HMGN3b have been proposed to regulate expression of glycine transporter gene 1 in the retina (West et al ., 2004). Dynamic expression pattern of HMGN1/2/3 genes in the eye suggest multiple roles of these proteins in gene regulation in the cornea, lens, and retina (Lucey et al ., 2008). …”

Section: Nucleosome-binding Proteins and Minor Core Histone Variantsmentioning

confidence: 99%

Epigenetic regulatory mechanisms in vertebrate eye development and disease

Cvekl

Mitton

2010

Heredity

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Eukaryotic DNA is organized as a nucleoprotein polymer termed chromatin with nucleosomes serving as its repetitive architectural units. Cellular differentiation is a dynamic process driven by activation and repression of specific sets of genes, partitioning the genome into transcriptionally active and inactive chromatin domains. Chromatin architecture at individual genes/loci may remain stable through cell divisions, from a single mother cell to its progeny during mitosis, and represents an example of epigenetic phenomena. Epigenetics refers to heritable changes caused by mechanisms distinct from the primary DNA sequence. Recent studies have shown a number of links between chromatin structure, gene expression, extracellular signaling, and cellular differentiation during eye development. This review summarizes recent advances in this field, and the relationship between sequence-specific DNA-binding transcription factors and their roles in recruitment of chromatin remodeling enzymes. In addition, lens and retinal differentiation is accompanied by specific changes in the nucleolar organization, expression of non-coding RNAs, and DNA methylation. Epigenetic regulatory mechanisms in ocular tissues represent exciting areas of research that have opened new avenues for understanding normal eye development, inherited eye diseases and eye diseases related to aging and the environment.

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Differential expression of the HMGN family of chromatin proteins during ocular development

Cited by 19 publications

References 28 publications

Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers

The Nucleosome Binding Protein HMGN3 Modulates the Transcription Profile of Pancreatic β Cells and Affects Insulin Secretion

Epigenetic regulatory mechanisms in vertebrate eye development and disease

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