HMGA regulates the global chromatin state and neurogenic potential in neocortical precursor cells

Kishi, Yusuke; Fujii, Y.; Hirabayashi, Yusuke; Gotoh, Yukiko

doi:10.1038/nn.3165

Cited by 125 publications

(145 citation statements)

References 46 publications

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“…Although H2AX does not affect nucleosome conformation, it has a destabilizing effect that is enhanced by its phosphorylation and results in an impaired linker histone H1 binding [29]. HMGA proteins were shown to dynamically compete with H1 for binding to the linker DNA, thereby loosening the chromatin [30,31]. In addition, displacement of H1 during the initial steps of gene activation has been reported [32].…”

Section: Discussionmentioning

confidence: 99%

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

et al. 2015

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The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFβ1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome.

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Section: Discussionmentioning

confidence: 99%

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

et al. 2015

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“…By binding to AT-rich DNA and interacting with histone-modifying enzymes and other proteins in enhanceosomes and chromatin, Hmga2 functions as a global epigenetic regulator (22,23). Using a dissociated prostate regeneration approach (24), we examined the contribution of Hmga2-modified stroma to prostate cancer initiation and progression and found that overexpression of stromal Hmga2 was extraordinarily potent and led to the development of multifocal PIN in a paracrine Wnt-dependent manner.…”

Section: Significancementioning

confidence: 99%

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Zong

Huang²,

Sankarasharma³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AThook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/β-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

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“…For example, unique sets of transcription factors are sequentially expressed in different populations of NPCs during brain development, including Pax6, Tbr2 (also known as Eomes) and Sox2 (Englund et al, 2005;Graham et al, 2003;Sessa et al, 2008). Epigenetic regulators modulate chromatin states to control NPC self-renewal and neurogenic potentials in a developmental stage-dependent manner (Kishi et al, 2012;Lim et al, 2009;Nishino et al, 2008). Although these studies have provided significant insights into the highly coordinated gene expression program at transcriptional levels for NPC behavior control, little is known about gene regulation at post-transcriptional levels for NPC self-renewal and brain development.…”

Section: Introductionmentioning

confidence: 99%

Lin28 promotes the proliferative capacity of neural progenitor cells in brain development

et al. 2015

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Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development.

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HMGA regulates the global chromatin state and neurogenic potential in neocortical precursor cells

Cited by 125 publications

References 46 publications

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

High mobility group protein-mediated transcription requires DNA damage marker γ-H2AX

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Lin28 promotes the proliferative capacity of neural progenitor cells in brain development

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