Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome

McCord, Rachel Patton; Nazario-Toole, Ashley E.; Zhang, Haoyue; Chines, Peter S.; Ye, Zhan; Erdos, Michael R.; Collins, Francis S.; Dekker, Job; Cao, Kan

doi:10.1101/gr.138032.112

Cited by 291 publications

(311 citation statements)

References 41 publications

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“…6A,B). Consistent with previous studies (Ly et al ., 2000; Park et al ., 2001; Csoka et al ., 2004; McCord et al ., 2013), there are more than 20% differentially expressed genes (up/down: 7.79%/14.18%) in HGPS cells vs. normal fibroblasts (Fig. 6A‐1).…”

Section: Resultsmentioning

confidence: 97%

“…Previous studies reported that the anchorage of progerin to the nuclear membrane caused a loss of perinuclear heterochromatin in HGPS cells (Goldman et al ., 2004; McCord et al ., 2013). Using TEM technology, we examined this progerin‐directed nuclear phenotype in mock‐ and MB‐treated HGPS cells and observed an obvious restoration of perinuclear heterochromatin organization after MB treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This deletion interferes with posttranslational processing by removing a key protease cleavage site, leading to permanent farnesylation and aberrant anchorage of the mutant lamin A, termed progerin, to the nuclear membrane (Eriksson et al ., 2003; Capell & Collins, 2006). The abnormal presence of progerin disrupts the integrity of the nucleoskeleton, causing high levels of nuclear abnormalities including nuclear blebbing, altered chromatin organization, transcriptional changes, and aberrant mitosis (Goldman et al ., 2002, 2004; Columbaro et al ., 2005; Liu et al ., 2005; Shumaker et al ., 2006; Cao et al ., 2007; Dechat et al ., 2007, 2008; McCord et al ., 2013; Stancheva & Schirmer, 2014). …”

Section: Introductionmentioning

confidence: 99%

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Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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SummaryHutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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“…A decrease in repression‐associated H3K27me3 (and an increased activity of the H3K27me3 demethylase KDM6A/UTX) is a key feature of the global chromatin reconfiguration occurring not only in somatic cells during the normal aging process but also in prematurely aging cells in HGPS and WS (Scaffidi & Misteli, 2005; Shah et al., 2013; Shumaker et al., 2006). In addition, landmark observations in Caenorhabditis elegans have linked gain of H3K27me3 (and loss of the H3K27me3 demethylase UTX‐1) to extended longevity, strongly suggesting that preserving high levels of H3K27me3 by inhibiting KDM6/UTX may be critical for maintaining youthfulness (Jin et al., 2011; Maures et al., 2011; McCord et al., 2013; Shah et al., 2013). Despite conflicting data from different model systems, there is a trend for increases in activating histone marks (e.g., H3K4m2/3, H3K36me3) and decreases in repressive histone marks (e.g., H3K9m2/3, H3K27me3) indicative of a more actively transcribed genome, which is consistent with a well‐recognized open chromatin conformation in aging cells and organisms that culminates in the so‐called heterochromatin loss model of aging (Pal & Tyler, 2016).…”

Section: Discussionmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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“…In addition, several reports have found progerin, and increasing levels of progerin, in normal cells over the course of normal aging (Scaffidi & Misteli, 2006; McClintock et al ., 2007; Cao et al ., 2007; Rodriguez et al ., 2009), which suggests a similar genetic mechanism in HGPS and normal aging. Moreover, genome‐scale expression profiling in cells from HGPS patients, as well as in physiological aging, has revealed widespread transcriptional misregulation in multiple mammalian tissues (Ly et al ., 2000; Csoka et al ., 2004; Zahn et al ., 2007; Scaffidi & Misteli, 2008; Cao et al ., 2011; McCord et al ., 2013). …”

Section: Introductionmentioning

confidence: 99%

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

et al. 2015

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SummaryAlternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome‐wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild‐type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3–3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P < 0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson–Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild‐type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.

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Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome

Cited by 291 publications

References 41 publications

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

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