Down-Regulation of Nucleosomal Binding Protein HMGN1 Expression during Embryogenesis Modulates Sox9 Expression in Chondrocytes

Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3122, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2006; 26(2):592-604. DOI: 10.1128/MCB.26.2.592-604.2006
Source: PubMed


We find that during embryogenesis the expression of HMGN1, a nuclear protein that binds to nucleosomes and reduces the compaction
of the chromatin fiber, is progressively down-regulated throughout the entire embryo, except in committed but continuously
renewing cell types, such as the basal layer of the epithelium. In the developing limb bud, the expression of HMGN1 is complementary
to Sox9, a master regulator of the chondrocyte lineage. In limb bud micromass cultures, which faithfully mimic in vivo chondrogenic
differentiation, loss of HMGN1 accelerates differentiation. Expression of wild-type HMGN1, but not of a mutant HMGN1 that
does not bind to chromatin, in Hmgn1−/− micromass cultures inhibits Sox9 expression and retards differentiation. Chromatin immunoprecipitation analysis reveals that HMGN1 binds to Sox9 chromatin in cells that are poised to express Sox9. Loss of HMGN1 elevates the amount of HMGN2 bound to Sox9, suggesting functional redundancy among these proteins. These findings suggest a role for HMGN1 in chromatin remodeling during
embryogenesis and in the activation of Sox9 during chondrogenesis.

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    • "Among the pathways altered by prenatal stress was HMGN1 (high-mobility group nucleosome binding domain 1), a nuclear protein involved in compaction of chromatin [78]–[79], histone modifications [80], DNA repair [81] and epigenetic regulation of neurodevelopmental diseases [82], such as Down syndrome [83], [82]. Interestingly, TS down-regulated Hmgn1 in motor cortex and offset the effects of cumulative stress on stroke recovery. "
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    ABSTRACT: Prenatal stress (PS) represents a critical variable affecting lifetime health trajectories, metabolic and vascular functions. Beneficial experiences may attenuate the effects of PS and its programming of health outcomes in later life. Here we investigated in a rat model (1) if PS modulates recovery following cortical ischemia in adulthood; (2) if a second hit by adult stress (AS) exaggerates stress responses and ischemic damage; and (3) if tactile stimulation (TS) attenuates the cumulative effects of PS and AS. Prenatally stressed and non-stressed adult male rats underwent focal ischemic motor cortex lesion and were tested in skilled reaching and skilled walking tasks. Two groups of rats experienced recurrent restraint stress in adulthood and one of these groups also underwent daily TS therapy. Animals that experienced both PS and AS displayed the most severe motor disabilities after lesion. By contrast, TS promoted recovery from ischemic lesion and reduced hypothalamic-pituitary-adrenal axis activity. The data also showed that cumulative effects of adverse and beneficial lifespan experiences interact with disease outcomes and brain plasticity through the modulation of gene expression. Microarray analysis of the lesion motor cortex revealed that cumulative PS and AS interact with genes related to growth factors and transcription factors, which were not affected by PS or lesion alone. TS in PS+AS animals reverted these changes, suggesting a critical role for these factors in activity-dependent motor cortical reorganization after ischemic lesion. These findings suggest that beneficial experience later in life can moderate adverse consequences of early programming to improve cerebrovascular health.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "). HMGNs have been studied extensively for their ability to modulate transcription (Furusawa et al., 2006; Zhu and Hansen, 2007; Ueda et al., 2009). HMGN5/NSBP1 is a typical member of the HMGN family which is localized to the nucleus and contains a functional NBD and a conserved motif in the C-terminus domain (Shirakawa et al., 2000). "
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    ABSTRACT: HMGN5 is a typical member of the HMGN (high mobility group nucleosome-binding protein) family which may function as a nucleosomal binding and transcriptional activating protein. Overexpression of HMGN5 has been observed in several human tumors but its role in tumorigenesis has not been fully clarified. To investigate its significance for human lung cancer progression, we successfully constructed a shRNA expression lentiviral vector in which sense and antisense sequences targeting the human HMGN5 were linked with a 9-nucleotide loop. Inhibitory effects of siRNA on endogenous HMGN5 gene expression and protein synthesis were demonstrated via real-time RT-PCR and western blotting. We found HMGN5 silencing to significantly inhibit A549 and H1299 cell proliferation assessed by MTT, BrdU incorporation and colony formation assays. Furthermore, flow cytometry analysis showed that specific knockdown of HMGN5 slowed down the cell cycle at the G0/G1 phase and decreased the populations of A549 and H1299 cells at the S and G2/M phases. Taken together, these results suggest that HMGN5 is directly involved in regulation cell proliferation in A549 and H1299 cells by influencing signaling pathways involved in cell cycle progression. Thus, our finding suggests that targeting HMGN5 may be an effective strategy for human lung cancer treatment.
    Preview · Article · Jul 2012 · Asian Pacific journal of cancer prevention: APJCP
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    • "In contrast to Mmp11, interdigital expression of RARb, Hmgn1, and Fgf18 in E13.5 autopods occurs specifically at the digit-interdigit junction rather than throughout the interdigital zone, thus correlating with Raldh2 expression in this domain. Hmgn1 and Fgf18 have previously been shown to be expressed in the interdigital zone and both are implicated in regulation of digit formation (Liu et al., 2002; Furusawa et al., 2006). We propose that RA synthesis becomes more predominately localized at the digitinterdigit junction as autopod development proceeds, leading to RARb upregulation which intensifies RA signaling at this junction, resulting in up-regulation of Hmgn1 and Fgf18. "
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    ABSTRACT: Previous studies on retinoic acid receptor (RAR) mutants suggested that retinoic acid (RA) is required for loss of interdigital mesenchyme during digit formation. Here, we report that the RA-generating enzyme retinaldehyde dehydrogenase-2 (Raldh2) is expressed in the interdigital mesenchyme whereas Cyp26b1, controlling RA degradation, is expressed in digits, limiting autopodal RA action to the interdigital zones. Embryonic day 13.5 Raldh2-/- mouse embryos lose expression of the RARE-lacZ RA-reporter transgene and matrix metalloproteinase-11 (Mmp11) throughout the interdigital mesenchyme, while expression of RARb, Fgf18, and high mobility group N1 (Hmgn1) is lost at the digit-interdigit junction. Raldh2-/- autopods exhibit reduced interdigital apoptosis associated with loss of Bmp7 expression, but Bmp2, Bmp4, Msx2, and Fgf8 were unaffected. Although interdigital expression of Hmgn1 was greatly down-regulated in Raldh2-/- autopods, complementary expression of Sox9 in digit cartilage was unaffected. Regulation of Hmgn1 and Fgf18 at the digit-interdigit junction suggests RA controls tissue remodeling as well as apoptosis.
    Full-text · Article · Feb 2010 · Developmental Dynamics
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