Functional interplay between MyoD and CTCF in regulating long-range chromatin interactions during differentiation

Battistelli, Cecilia; Busanello, Anna; Maione, Rossella

doi:10.1242/jcs.149427

Cited by 32 publications

(40 citation statements)

References 59 publications

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“…Crosslinked chromatin was subject to digestion and ligation, after which hybrid fragments, deriving from the ligation of Cdkn1c promoter and KvDMR1 sequences, were amplified as previously described. 23,24 The results reported in Fig. 2C show that 5-AZA treatment, in concomitance with decreased DNA methylation and increased MyoD binding, also caused a reduction of the interaction frequency between Cdkn1c promoter and KvDMR1, denoting the release of the chromatin loop.…”

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 87%

“…19 MyoD is the prototypical master regulator of differentiation 20 and induces Cdkn1c expression through a complex mechanism involving, on one hand, the mediation of MyoD-induced factors, which interact with Cdkn1c promoter 21,22 and, on the other hand, the direct interaction of MyoD with KvDMR1. 23,24 In particular, we found that, in undifferentiated myoblasts, KvDMR1 is involved in a repressive long-range chromatin interaction with Cdkn1c promoter, mediated by CTCF. Upon differentiation stimuli, MyoD binds to an E-box-like sequence adjacent to a CTCF binding site within KvDMR1, causing the disruption of the chromatin loop and the induction of maternal Cdkn1c expression.…”

mentioning

confidence: 80%

“…These cell types, that we termed unresponsive in comparison with the normally responsive cells, represented a very useful experimental tool to highlight the existence of cis-acting constraints preventing Cdkn1c expression 21,22 and to reveal the functional importance of the MyoD binding to KvDMR1. 23,24 In particular, we found that, in unresponsive cells, MyoD is unable to interact with KvDMR1-chromatin and promote the release of the CTCFmediated loop.…”

mentioning

confidence: 83%

“…19,21,22 In the present work, we employed immortalized mouse C57BL/6 as responsive and C3H10T1/2 as unresponsive fibroblasts, the 2 cell types in which we had previously examined in most detail the role of MyoD in regulating the long-range interaction between KvDMR1 and Cdkn1c promoter. 23,24 Comparison of the promoter 21 and KvDMR1 ( Supplementary Fig. 1) sequences between the 2 cell types revealed a complete identity, thus suggesting the existence of some epigenetic restriction in unresponsive cells.…”

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 96%

“…23 Cdkn1c silencing has been observed in several cancer cell types and has been found to contribute to their malignant phenotype. 1 A number of studies, addressing the molecular mechanisms underlying Cdkn1c repression, focused on the gain of repressive epigenetic modifications at the promoter or on the loss of KvDMR1 function resulting in maternal expression of Kcnq1ot1 and biallelic silencing of Cdkn1c.…”

Section: Differential H3k9me2 Enrichment Marks Kvdmr1 In Cancer Cellsmentioning

confidence: 99%

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A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

et al. 2016

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The cdk inhibitor p57 kip2 , encoded by the Cdkn1c gene, plays a critical role in mammalian development and in the differentiation of several tissues. Cdkn1c protein levels are carefully regulated via imprinting and other epigenetic mechanisms affecting both the promoter and distant regulatory elements, which restrict its expression to particular developmental phases or specific cell types. Inappropriate activation of these regulatory mechanisms leads to Cdkn1c silencing, causing growth disorders and cancer. We have previously reported that, in skeletal muscle cells, induction of Cdkn1c expression requires the binding of the bHLH myogenic factor MyoD to a long-distance regulatory element within the imprinting control region KvDMR1. Interestingly, MyoD binding to KvDMR1 is prevented in myogenic cell types refractory to the induction of Cdkn1c. In the present work, we took advantage of this model system to investigate the epigenetic determinants of the differential interaction of MyoD with KvDMR1. We show that treatment with the DNA demethylating agent 5-azacytidine restores the binding of MyoD to KvDMR1 in cells unresponsive to Cdkn1c induction. This, in turn, promotes the release of a repressive chromatin loop between KvDMR1 and Cdkn1c promoter and, thus, the upregulation of the gene. Analysis of the chromatin status of Cdkn1c promoter and KvDMR1 in unresponsive compared to responsive cell types showed that their differential responsiveness to the MyoD-dependent induction of the gene does not involve just their methylation status but, rather, the differential H3 lysine 9 dimethylation at KvDMR1. Finally, we report that the same histone modification also marks the KvDMR1 region of human cancer cells in which Cdkn1c is silenced. On the basis of these results, we suggest that the epigenetic status of KvDMR1 represents a critical determinant of the cell type-restricted expression of Cdkn1c and, possibly, of its aberrant silencing in some pathological conditions.

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Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 87%

mentioning

confidence: 80%

mentioning

confidence: 83%

Section: -Aza Treatment Restores the Functional Interaction Of Myod mentioning

confidence: 96%

Section: Differential H3k9me2 Enrichment Marks Kvdmr1 In Cancer Cellsmentioning

confidence: 99%

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A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

et al. 2016

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Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder

Chen

Yuan

et al. 2019

American J of Med Genetics Pt C

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CCCTC‐binding factor (CTCF) is an important regulator for global genomic organization and gene expression. CTCF gene had been implicated in a novel disorder characterized by intellectual disability, feeding difficulty, developmental delay and microcephaly. So far, four patients have been reported with de novo CTCF mutations. We reported three additional Chinese patients with de novo variants in CTCF. The new evidence helped to establish the clinical validity between CTCF and the emerging disorder. We described the consistent phenotypes shared by all patients and revealed additional clinical features such as delayed or abnormal teeth development and a unique pattern of the eyebrow that may help to define a potential recognizable neurodevelopmental disorder. We also reported the first CTCF patient treated with recombinant human growth hormone. Follow‐up and more case studies will further our understanding to the clinical presentations of this novel disorder and the prognosis of patients with this disorder.

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Single nucleotide polymorphisms linked to mitochondrial uncoupling protein genes UCP2 and UCP3 affect mitochondrial metabolism and healthy aging in female nonagenarians

et al. 2016

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Energy expenditure decreases with age, but in the oldest-old, energy demand for maintenance of body functions increases with declining health. Uncoupling proteins have profound impact on mitochondrial metabolic processes; therefore, we focused attention on mitochondrial uncoupling protein genes. Alongside resting metabolic rate (RMR), two SNPs in the promoter region of UCP2 were associated with healthy aging. These SNPs mark potential binding sites for several transcription factors; thus, they may affect expression of the gene. A third SNP in the 3′-UTR of UCP3 interacted with RMR. This UCP3 SNP is known to impact UCP3 expression in tissue culture cells, and it has been associated with body weight and mitochondrial energy metabolism. The significant main effects of the UCP2 SNPs and the interaction effect of the UCP3 SNP were also observed after controlling for fat-free mass (FFM) and physical-activity related energy consumption. The association of UCP2/3 with healthy aging was not found in males. Thus, our study provides evidence that the genetic risk factors for healthy aging differ in males and females, as expected from the differences in the phenotypes associated with healthy aging between the two sexes. It also has implications for how mitochondrial function changes during aging.

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Functional interplay between MyoD and CTCF in regulating long-range chromatin interactions during differentiation

Cited by 32 publications

References 59 publications

A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder

Single nucleotide polymorphisms linked to mitochondrial uncoupling protein genes UCP2 and UCP3 affect mitochondrial metabolism and healthy aging in female nonagenarians

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