A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts

Sidler, Corinne; Wóycicki, Rafał; Li, Dongping; Wang, Bo; Kovalchuk, Igor; Kovalchuk, Olga

doi:10.18632/aging.100678

Cited by 42 publications

(34 citation statements)

References 63 publications

(91 reference statements)

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“…Men1 is related to histone marks H3K9me3 and H3K4me3 [24, 25], and Suv39h1 is a regulator for H3K9me3 [26] (Figure 2a). As H3K9me3 has been known as a repressive marker, we postulated that Men1 might inhibit reprogramming through activating H3K9 methyltransferase activity.…”

Section: Resultsmentioning

confidence: 99%

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

et al. 2016

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Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene Ebf1 involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.

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Section: Resultsmentioning

confidence: 99%

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

et al. 2016

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“…After stratifying our cohort according to cytogenetics parameters, we observed that decreasing SUV39H1 expression is significantly associated with the acquisition of cytogenetic alterations. Indeed, it has been demonstrated that inhibition of SUV39H1 promotes genome instability [Sidler et al, ], which in part occurs by the induction of aurora B kinase activity [Chu et al, ], a protein that promotes chromosomal instability and has been associated with the development of several types of cancer [Tatsuka et al, ; Ota et al, ; Lucena‐Araujo et al, ]. The demonstration that SUV39H1 is associated with genomic stability in CLL is particularly important because chromosomal aberrations and genomic complexity in CLL are powerful marker for the discrimination of patients with aggressive disease and short overall survival [Mayr et al, ; Ouillette et al, ].…”

Section: Discussionmentioning

confidence: 99%

Aberrant levels of SUV39H1 and SUV39H2 methyltransferase are associated with genomic instability in chronic lymphocytic leukemia

Silva

Rabello

Bravo

et al. 2017

Environ and Mol Mutagen

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Chromosomal alterations are commonly detected in patients with chronic lymphocytic leukemia (CLL) and impact disease pathogenesis, prognosis, and progression. Telomerase expression (hTERT), its activity and the telomere length are other important predictors of survival and multiple outcomes in CLL. SUV39H and SUV420H enzymes are histone methyltransferases (HMTases) involved in several cellular processes, including regulation of telomere length, heterochromatin organization, and genome stability. Here, we investigated whether SUV39H1, SUV39H2, SUV420H1, SUV420H2, and hTERT are associated with genomic instability of CLL. SUV39H (1/2), SUV420H (1/2), and hTERT expression was determined in 59 CLL samples by real time PCR. In addition, ZAP-70 protein expression was evaluated by Flow Cytometry and patients' karyotype was defined by Cytogenetic Analysis. Low expression of SUV39H1 was associated with the acquisition of altered and complex karyotypes. Conversely, high expression of SUV39H2 correlated with cytogenetic abnormalities in CLL patients. The pattern of karyotypic alterations differed in samples with detectable or undetectable hTERT expression. Furthermore, hTERT expression in CLL showed a correlation with transcript levels of SUV39H2, which, in part, can explain the association between SUV39H2 expression and cytogenetic abnormalities. Moreover, SUV39H1 correlated with SUV420H1 expression while SUV420H2 was associated with all other investigated HMTases. Our data show that the differential expression of SUV39H1 and SUV39H2 is associated with genomic instability and that the modulation of these HMTases can be an attractive approach to prevent CLL evolution. Environ. Mol. Mutagen. 58:654-661, 2017. © 2017 Wiley Periodicals, Inc.

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“…Our previous results showed such an induction of transcriptional activation of the pericentric satellite regions to be associated with the reduction of H3K9me3 levels in those regions during replicative senescence (Sidler et al, 2014), suggesting that the heterochromatin relaxation in those regions may contribute to genomic instability and growth arrest.…”

Section: Discussionmentioning

confidence: 92%

“…Our previous results showed that SUV39H1 overexpression in senescent cells induced cell division, while SUV39H1 inhibition in dividing cells slightly inhibited cell division (Sidler et al, 2014). The overexpression of SUV39H1 prior to exposure to IR compensated for the radiation-induced downregulation of SUV39H1 , preventing the induction of senescence.…”

Section: Discussionmentioning

confidence: 95%

SUV39H1 downregulation induces deheterochromatinization of satellite regions and senescence after exposure to ionizing radiation

Sidler¹,

Li²,

Wang³

et al. 2014

Front. Genet.

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While the majority of cancer patients are exposed to ionizing radiation during diagnostic and therapeutic procedures, age-dependent differences in radiation sensitivity are not yet well understood. Radiation sensitivity is characterized by the appearance of side effects to radiation therapy, such as secondary malignancies, developmental deficits, and compromised immune function. However, the knowledge of the molecular mechanisms that trigger these side effects is incomplete. Here we used an in vitro system and showed that low-senescent normal human diploid fibroblasts (WI-38) senesce in response to 5 Gy IR, while highly senescent cultures do not show changes in cell cycle regulation and only a slight increase in the percentage of senescent cells. Our study shows that this is associated with changes in the expression of genes responsible for cell cycle progression, apoptosis, DNA repair, and aging, as well as transcriptional and epigenetic regulators. Furthermore, we propose a role of the downregulation of SUV39H1 expression, a histone methyltransferase that specifically trimethylates H3K9, and the corresponding reduction in H3K9me3 levels in the establishment of IR-induced senescence.

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A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts

Cited by 42 publications

References 63 publications

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

Aberrant levels of SUV39H1 and SUV39H2 methyltransferase are associated with genomic instability in chronic lymphocytic leukemia

SUV39H1 downregulation induces deheterochromatinization of satellite regions and senescence after exposure to ionizing radiation

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