scholarly journals PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1735
Author(s):  
Spartaco Santi ◽  
Vittoria Cenni ◽  
Cristina Capanni ◽  
Giovanna Lattanzi ◽  
Elisabetta Mattioli
Keyword(s):  
Muscular Dystrophy ◽  
Early Phase ◽  
Myogenic Differentiation ◽  
Nuclear Lamina ◽  
Muscle Differentiation ◽  
Lamin A ◽  
Histone Deacetylase 2 ◽  
Muscle Gene Expression ◽  
Muscle Gene ◽  
Human Muscle Cells

Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation of lamin A/C-HDAC2 interaction in human muscle cells. We present evidence that HDAC2 binding to lamin A/C is related to HDAC2 acetylation on lysine 75 and expression of p300-CBP associated factor (PCAF), an acetyltransferase known to acetylate HDAC2. Our findings show that lamin A and farnesylated prelamin A promote PCAF recruitment to the nuclear lamina and lamin A/C binding in human myoblasts committed to myogenic differentiation, while protein interaction is decreased in differentiating myotubes. Interestingly, PCAF translocation to the nuclear envelope, as well as lamin A/C-PCAF interaction, are reduced by transient expression of lamin A mutated forms causing Emery Dreifuss muscular dystrophy. Consistent with this observation, lamin A/C interaction with both PCAF and HDAC2 is significantly reduced in Emery–Dreifuss muscular dystrophy myoblasts. Overall, these results support the view that, by recruiting PCAF and HDAC2 in a molecular platform, lamin A/C might contribute to regulate their epigenetic activity required in the early phase of muscle differentiation.

scholarly journals A heterochromatic histone methyltransferase lowers nucleosome occupancy at euchromatic promoters

2018 ◽  
Author(s):  
H.M. Chen ◽  
T.B. Sackton ◽  
B. Mutlu ◽  
J. Wang ◽  
S. Keppler-Ross ◽  
...  
Keyword(s):  
Nucleosome Occupancy ◽  
Histone H3 ◽  
Nuclear Lamina ◽  
Regulatory Elements ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
C Elegans ◽  
Muscle Gene Expression ◽  
Chromatin Configuration ◽  
Muscle Gene

AbstractH3K9me3 (histone H3 modified with tri-methylation at lysine 9) is a hallmark of transcriptional silencing and heterochromatin. However, its global effects on the genome, including euchromatin, are less well understood. Here we develop Formaldehyde-Assisted Identification of Regulatory Elements (FAIRE) for C. elegans to examine the chromatin configuration of mutants that lack virtually all H3K9me3, while leaving H3K9me1 and H3K9me2 intact. We find that nucleosomes are mildly disrupted, and levels of H3K9me2 and H3K27me3 rise in mutant embryos. In addition to these expected changes, the most dramatic change occurs in euchromatin: many regions encompassing transcription start sites (TSSs) gain an average of two nucleosomes in mutants. The affected regions normally lack H3K9me3, revealing a locus non-autonomous role for H3K9me3. Affected TSSs are associated with genes that are active in epithelia and muscles, and implicated in development, locomotion, morphogenesis and transcription. Mutant embryos develop normally under ideal laboratory conditions but die when challenged, with defects in morphogenesis and development. Our findings reveal that H3K9me3 protects transcription start sites within euchromatin from nucleosome deposition. These results may be relevant to mammals, where diseases that disrupt the nuclear lamina and heterochromatin can alter epithelial and muscle gene expression.

scholarly journals miR-155 Inhibits Expression of the MEF2A Protein to Repress Skeletal Muscle Differentiation

2011 ◽  
Vol 286 (41) ◽  
pp. 35339-35346 ◽  
Author(s):  
Hee Young Seok ◽  
Mariko Tatsuguchi ◽  
Thomas E. Callis ◽  
Aibin He ◽  
William T. Pu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Rnas ◽  
Myogenic Differentiation ◽  
Regulation Of Gene Expression ◽  
Myoblast Differentiation ◽  
Transcriptional Level ◽  
Muscle Gene Expression ◽  
Important Regulator ◽  
Non Coding Rnas ◽  
Muscle Gene

microRNAs (miRNAs) are 21–23-nucleotide non-coding RNAs. It has become more and more evident that this class of small RNAs plays critical roles in the regulation of gene expression at the post-transcriptional level. MEF2A is a member of the MEF2 (myogenic enhancer factor 2) family of transcription factors. Prior report showed that the 3′-untranslated region (3′-UTR) of the Mef2A gene mediated its repression; however, the molecular mechanism underlying this intriguing observation was unknown. Here, we report that MEF2A is repressed by miRNAs. We identify miR-155 as one of the primary miRNAs that significantly represses the expression of MEF2A. We show that knockdown of the Mef2A gene by siRNA impairs myoblast differentiation. Similarly, overexpression of miR-155 leads to the repression of endogenous MEF2A expression and the inhibition of myoblast differentiation. Most importantly, reintroduction of MEF2A in miR-155 overexpressed myoblasts was able to partially rescue the miR-155-induced myoblast differentiation defect. Our data therefore establish miR-155 as an important regulator of MEF2A expression and uncover its function in muscle gene expression and myogenic differentiation.

FHL1B Interacts with Lamin A/C and Emerin at the Nuclear Lamina and is Misregulated in Emery-Dreifuss Muscular Dystrophy

2016 ◽  
Vol 3 (4) ◽  
pp. 497-510 ◽  
Author(s):  
Esma Ziat ◽  
Kamel Mamchaoui ◽  
Maud Beuvin ◽  
Isabelle Nelson ◽  
Feriel Azibani ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Lamina ◽  
Lamin A

scholarly journals The Genes, Proteins, and the Cell Biological Processes Underlying Emery-Dreifuss Muscular Dystrophy

2017 ◽  
Vol 6 (1) ◽  
pp. 14-18
Author(s):  
Elise Alexandra Kikis ◽  
Megan Elizabeth Mastey
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Autosomal Dominant ◽  
Nuclear Lamina ◽  
Autosomal Recessive Inheritance ◽  
Envelope Proteins ◽  
Lamin A ◽  
Dominant Form ◽  
Specific Effects ◽  
Autosomal Dominant Form

Emery-Dreifuss Muscular Dystrophy (EDMD) is a type of muscular dystrophy characterized by contractures, or shortening of muscles or joints in the elbows and Achilles tendons, muscle wasting and weakness as well as cardiomyopathy. There are two main forms of inherited EDMD, X-linked recessive and autosomal dominant. There is also a rarer form of autosomal recessive inheritance with only a few cases ever reported. The X-linked form of EDMD is caused by mutation of the STA gene that encodes the protein emerin, while the autosomal dominant form is caused by a missense mutation on the LMNA gene, which encodes lamin A/C proteins. Both emerin and lamin A/C are nuclear envelope proteins that interact with other proteins to create a connective network that attaches the nuclear lamina to the cytoskeleton. These nuclear envelope proteins interact via accessory proteins to chromatin and also thereby stimulate gene expression. The exact mechanism of how mutations in these genes lead to muscular dystrophy is not well understood. The “structural hypothesis,” states that the absence of these envelope proteins result in a weakened cell and would eventually end in nuclear disruption. The “gene regulatory hypothesis” states that emerin and lamin may be transcription factors whose absence results in tissue-specific effects. This review will addresses these hypotheses, describes what is known about the cell and molecular biology underlying EDMD and considers recent as advances in therapeutics.

The cell cycle dependent mislocalisation of emerin may contribute to the Emery-Dreifuss muscular dystrophy phenotype

2002 ◽  
Vol 115 (2) ◽  
pp. 341-354 ◽  
Author(s):  
Elizabeth A. L. Fairley ◽  
Andrew Riddell ◽  
Juliet A. Ellis ◽  
John Kendrick-Jones
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Transmembrane Domain ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Wild Type ◽  
Cycle Dependent ◽  
Mutant Forms

Emerin is the nuclear membrane protein defective in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). The majority of X-EDMD patients have no detectable emerin. However, there are cases that produce mutant forms of emerin, which can be used to study its function. Our previous studies have shown that the emerin mutants S54F, P183T, P183H, Del95-99, Del236-241 (identified in X-EDMD patients) are targeted to the nuclear membrane but to a lesser extent than wild-type emerin. In this paper, we have studied how the mislocalisation of these mutant emerins may affect nuclear functions associated with the cell cycle using flow cytometry and immunofluorescence microscopy. We have established that cells expressing the emerin mutant Del236-241 (a deletion in the transmembrane domain), which was mainly localised in the cytoplasm, exhibited an aberrant cell cycle length. Thereafter, by examining the intracellular localisation of endogenously expressed lamin A/C and exogenously expressed wild-type and mutant forms of emerin after a number of cell divisions, we determined that the mutant forms of emerin redistributed endogenous lamin A/C. The extent of lamin A/C redistribution correlated with the amount of EGFP-emerin that was mislocalised. The amount of EGFP-emerin mislocalized, in turn, was associated with alterations in the nuclear envelope morphology. The nuclear morphology and redistribution of lamin A/C was most severely affected in the cells expressing the emerin mutant Del236-241.It is believed that emerin is part of a novel nuclear protein complex consisting of the barrier-to-autointegration factor (BAF), the nuclear lamina, nuclear actin and other associated proteins. The data presented here show that lamin A/C localisation is dominantly directed by its interaction with certain emerin mutants and perhaps wild-type emerin as well. These results suggest that emerin links A-type lamins to the nuclear envelope and that the correct localisation of these nuclear proteins is important for maintaining cell cycle timing.

scholarly journals Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle.

1996 ◽  
Vol 135 (2) ◽  
pp. 441-456 ◽  
Author(s):  
B G Novitch ◽  
G J Mulligan ◽  
T Jacks ◽  
A B Lassar
Keyword(s):  
Cell Cycle ◽  
Skeletal Muscle ◽  
Cell Cycle Progression ◽  
Muscle Differentiation ◽  
Mitotic Catastrophe ◽  
Skeletal Muscle Differentiation ◽  
Differentiation Markers ◽  
Muscle Gene Expression ◽  
Retinoblastoma Tumor ◽  
Muscle Gene

Viral oncoproteins that inactivate the retinoblastoma tumor suppressor protein (pRb) family both block skeletal muscle differentiation and promote cell cycle progression. To clarify the dependence of terminal differentiation on the presence of the different pRb-related proteins, we have studied myogenesis using isogenic primary fibroblasts derived from mouse embryos individually deficient for pRb, p107, or p130. When ectopically expressed in fibroblasts lacking pRb, MyoD induces an aberrant skeletal muscle differentiation program characterized by normal expression of early differentiation markers such as myogenin and p21, but attenuated expression of late differentiation markers such as myosin heavy chain (MHC). Similar defects in MHC expression were not observed in cells lacking either p107 or p130, indicating that the defect is specific to the loss of pRb. In contrast to wild-type, p107-deficient, or p130-deficient differentiated myocytes that are permanently withdrawn from the cell cycle, differentiated myocytes lacking pRb accumulate in S and G2 phases and express extremely high levels of cyclins A and B, cyclin-dependent kinase (Cdk2), and Cdc2, but fail to readily proceed to mitosis. Administration of caffeine, an agent that removes inhibitory phosphorylations on inactive Cdc2/cyclin B complexes, specifically induced mitotic catastrophe in pRb-deficient myocytes, consistent with the observation that the majority of pRb-deficient myocytes arrest in S and G2. Together, these findings indicate that pRb is required for the expression of late skeletal muscle differentiation markers and for the inhibition of DNA synthesis, but that a pRb-independent mechanism restricts entry of differentiated myocytes into mitosis.

scholarly journals Transforming Growth Factor-β (TGF-β1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression

2007 ◽  
Vol 283 (3) ◽  
pp. 1324-1333 ◽  
Author(s):  
Simone Kennard ◽  
Hua Liu ◽  
Brenda Lilly
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Muscle Differentiation ◽  
Muscle Gene Expression ◽  
Smooth Muscle Differentiation ◽  
Muscle Gene ◽  
Tgf Β1

Select signaling pathways have emerged as key players in regulating smooth muscle gene expression during myofibroblast and smooth muscle differentiation, an event that is important for wound healing and vascular remodeling. These include the transforming growth factor-β (TGF-β1) signaling cascade, which has been assigned multiple roles in these cells, and the Notch pathway. Notch family members have been implicated in governing cell fate in a variety of cells; however, the mechanisms are not well understood. We sought to explore how these prominent signaling mediators regulate differentiation, and in particular, how they might converge to control the transcription of smooth muscle genes. Using TGF-β1 to induce the differentiation of 10T1/2 fibroblasts, we investigated the specific function of Notch3. Overexpression of activated Notch3 caused repression of TGF-β1-induced smooth muscle-specific genes, whereas knockdown of Notch3 by small interfering RNA did not convincingly alter their expression. Surprisingly, the addition of TGF-β1 caused a significant decrease in Notch3 RNA and protein and a reciprocal increase in Hes1 gene transcription. The repression of Notch3 was mediated by SMAD activity and p38 mitogen-activated protein (MAP) kinase, whereas analysis of the Hes1 promoter revealed direct activation by Smad2 but not Smad3. Furthermore, the Hes1 repressor protein augmented Smad3 transactivation of the SM22α promoter. These results offer a novel mechanism by which TGF-β1 promotes the expression of smooth muscle differentiation genes through the inhibition of Notch3 and activation of Hes1.

scholarly journals The histone methyltransferase Set7/9 promotes myoblast differentiation and myofibril assembly

2011 ◽  
Vol 194 (4) ◽  
pp. 551-565 ◽  
Author(s):  
Yazhong Tao ◽  
Ronald L. Neppl ◽  
Zhan-Peng Huang ◽  
Jianfu Chen ◽  
Ru-Hang Tang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
Histone Methyltransferase ◽  
Contractile Proteins ◽  
Dominant Negative ◽  
Myoblast Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Muscle Gene Expression

The molecular events that modulate chromatin structure during skeletal muscle differentiation are still poorly understood. We report in this paper that expression of the H3-K4 histone methyltransferase Set7 is increased when myoblasts differentiate into myotubes and is required for skeletal muscle development, expression of muscle contractile proteins, and myofibril assembly. Knockdown of Set7 or expression of a dominant-negative Set7 mutant impairs skeletal muscle differentiation, accompanied by a decrease in levels of histone monomethylation (H3-K4me1). Set7 directly interacts with MyoD to enhance expression of muscle differentiation genes. Expression of myocyte enhancer factor 2 and genes encoding contractile proteins is decreased in Set7 knockdown myocytes. Furthermore, we demonstrate that Set7 also activates muscle gene expression by precluding Suv39h1-mediated H3-K9 methylation on the promoters of myogenic differentiation genes. Together, our experiments define a biological function for Set7 in muscle differentiation and provide a molecular mechanism by which Set7 modulates myogenic transcription factors during muscle differentiation.

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