A cytoskeletal function for PBRM1 reading methylated microtubules

Epigenetic effectors “read” marks “written” on chromatin to regulate function and fidelity of the genome. Here, we show that this coordinated read-write activity of the epigenetic machinery extends to the cytoskeleton, with PBRM1 in the PBAF chromatin remodeling complex reading microtubule methyl marks written by the SETD2 histone methyltransferase. PBRM1 binds SETD2 methyl marks via BAH domains, recruiting PBAF components to the mitotic spindle. This read-write activity was required for normal mitosis: Loss of SETD2 methylation or pathogenic BAH domain mutations disrupt PBRM1 microtubule binding and PBAF recruitment and cause genomic instability. These data reveal PBRM1 functions beyond chromatin remodeling with domains that allow it to integrate chromatin and cytoskeletal activity via its acetyl-binding BD and methyl-binding BAH domains, respectively. Conserved coordinated activity of the epigenetic machinery on the cytoskeleton opens a previously unknown window into how chromatin remodeler defects can drive disease via both epigenetic and cytoskeletal dysfunction.

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Loss of the Epigenetic Tumor Suppressor SNF5 Leads to Cancer without Genomic Instability

Molecular and Cellular Biology ◽

10.1128/mcb.00658-08 ◽

2008 ◽

Vol 28 (20) ◽

pp. 6223-6233 ◽

Cited By ~ 94

Author(s):

Elizabeth S. McKenna ◽

Courtney G. Sansam ◽

Yoon-Jae Cho ◽

Heidi Greulich ◽

Julia A. Evans ◽

...

Keyword(s):

Tumor Suppressor ◽

Genomic Instability ◽

Chromatin Remodeling ◽

Suppressor Activity ◽

Dna Damaging Agents ◽

Chromatin Remodeling Complex ◽

Core Member ◽

Aggressive Cancer ◽

Tumor Suppressor Activity ◽

Tumor Phenotype

ABSTRACT There is a growing appreciation of the role that epigenetic alterations can play in oncogenesis. However, given the large number of genetic anomalies present in most cancers, it has been difficult to evaluate the extent to which epigenetic changes contribute to cancer. SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the epigenome as a core member of the SWI/SNF chromatin remodeling complex. While the SWI/SNF complex displays potent tumor suppressor activity, it is unknown whether this activity is exerted genetically via maintenance of genome integrity or epigenetically via transcriptional regulation. Here we show that Snf5-deficient primary cells do not show altered sensitivity to DNA damaging agents, defects in γ-H2AX induction, or an abrogated DNA damage checkpoint. Further, the aggressive malignancies that arise following SNF5 loss are diploid and genomically stable. Remarkably, we demonstrate that most human SNF5-deficient cancers lack genomic amplifications/deletions and, aside from SNF5 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays. Finally, we show that epigenetically based changes in transcription that occur following SNF5 loss correlate with the tumor phenotype. Collectively, our results provide novel insight into the mechanisms of oncogenesis by demonstrating that disruption of a chromatin remodeling complex can largely, if not completely, substitute for genomic instability in the genesis of aggressive cancer.

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A Cytoskeletal Function for PBRM1 Reading Methylated Microtubules

10.1101/2020.04.21.053942 ◽

2020 ◽

Cited By ~ 1

Author(s):

Menuka Karki ◽

Rahul K. Jangid ◽

Riyad N.H. Seervai ◽

Jean-Philippe Bertocchio ◽

Takashi Hotta ◽

...

Keyword(s):

Mass Spectrometry ◽

Cell Division ◽

Posttranslational Modification ◽

Mitotic Spindle ◽

Spindle Pole ◽

Dual Function ◽

New Paradigm ◽

Chromatin Remodelers ◽

Epigenetic Machinery ◽

Cytoskeletal Function

AbstractThe chromatin modifier SETD2 was recently shown to be a dual-function methyltransferase that “writes” methyl marks on both chromatin and the mitotic spindle, revealing α-tubulin methylation as a new posttranslational modification of microtubules. Here, we report the first cytoskeletal “reader” for this SETD2 methyl mark: the polybromo protein PBRM1. We found PBRM1 directly binds the α-Tub-K40me3 mark on tubulin, and localizes to the mitotic spindle and spindle pole during cell division. PBRM1 can assemble a PBAF complex in the absence of chromatin as revealed by mass spectrometry, and can recruit other PBAF complex components including SMARCA4 and ARID2 to α-tubulin. In addition to PBRM1, other PBAF components were also localized to the mitotic spindle and spindle pole. This PBAF localization was dependent on recruitment to microtubules by PBRM1, and loss of spindle-associated PBRM1/PBAF led to genomic instability as assessed by increased formation of micronuclei. These data reveal a previously unknown function for PBRM1 beyond its role remodeling chromatin, and expand the repertoire of chromatin remodelers involved in writing and reading methyl marks on the cytoskeleton. The results of this study lay the foundation for a new paradigm for the epigenetic machinery as chromatocytoskeletal modifiers, with coordinated nuclear and cytoskeletal functions.

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Faculty Opinions recommendation of The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014780.194751 ◽

2003 ◽

Author(s):

Giovanni Neri

Keyword(s):

Nuclear Receptor ◽

Chromatin Remodeling ◽

Williams Syndrome ◽

Chromatin Remodeling Complex

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Regulation of Egr1 Target Genes by the Nurd Chromatin Remodeling Complex

10.21236/ada486655 ◽

2008 ◽

Author(s):

John Svaren

Keyword(s):

Chromatin Remodeling ◽

Target Genes ◽

Chromatin Remodeling Complex

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Actin-Related Protein 4 Interacts with PIE1 and Regulates Gene Expression in Arabidopsis

Genes ◽

10.3390/genes12040520 ◽

2021 ◽

Vol 12 (4) ◽

pp. 520

Author(s):

Wenfeng Nie ◽

Jinyu Wang

Keyword(s):

Gene Expression ◽

Plant Growth ◽

Chromatin Remodeling ◽

Leaf Size ◽

Early Flowering ◽

Physical Interaction ◽

Loss Of Function ◽

Single Nucleotide Change ◽

Chromatin Remodeling Complex ◽

Related Proteins

As essential structural components of ATP-dependent chromatin-remodeling complex, the nucleolus-localized actin-related proteins (ARPs) play critical roles in many biological processes. Among them, ARP4 is identified as an integral subunit of chromatin remodeling complex SWR1, which is conserved in yeast, humans and plants. It was shown that RNAi mediated knock-down of Arabidopsis thaliana ARP4 (AtARP4) could affect plant development, specifically, leading to early flowering. However, so far, little is known about how ARP4 functions in the SWR1 complex in plant. Here, we identified a loss-of-function mutant of AtARP4 with a single nucleotide change from glycine to arginine, which had significantly smaller leaf size. The results from the split luciferase complementation imaging (LCI) and yeast two hybrid (Y2H) assays confirmed its physical interaction with the scaffold and catalytic subunit of SWR1 complex, photoperiod-independent early flowering 1 (PIE1). Furthermore, mutation of AtARP4 caused altered transcription response of hundreds of genes, in which the number of up-regulated differentially expressed genes (DEGs) was much larger than those down-regulated. Although most DEGs in atarp4 are related to plant defense and response to hormones such as salicylic acid, overall, it has less overlapping with other swr1 mutants and the hta9 hta11 double-mutant. In conclusion, our results reveal that AtARP4 is important for plant growth and such an effect is likely attributed to its repression on gene expression, typically at defense-related loci, thus providing some evidence for the coordination of plant growth and defense, while the regulatory patterns and mechanisms are distinctive from other SWR1 complex components.

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Interplay of BAF and MLL4 promotes cell type-specific enhancer activation

Nature Communications ◽

10.1038/s41467-021-21893-y ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Young-Kwon Park ◽

Ji-Eun Lee ◽

Zhijiang Yan ◽

Kaitlin McKernan ◽

Tommy O’Haren ◽

...

Keyword(s):

Cell Differentiation ◽

Chromatin Remodeling ◽

Direct Evidence ◽

Cell Type ◽

Chromatin Regulators ◽

Chromatin Remodeling Complex ◽

Histone H3k4 ◽

Cell Type Specific ◽

Pioneer Transcription Factor ◽

Factor C

AbstractCell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators. The SWI/SNF chromatin remodeling complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) are both implicated in enhancer activation. However, the interplay between BAF and MLL4 in enhancer activation remains unclear. Using adipogenesis as a model system, we identify BAF as the major SWI/SNF complex that colocalizes with MLL4 and LDTFs on active enhancers and is required for cell differentiation. In contrast, the promoter enriched SWI/SNF complex PBAF is dispensable for adipogenesis. By depleting BAF subunits SMARCA4 (BRG1) and SMARCB1 (SNF5) as well as MLL4 in cells, we show that BAF and MLL4 reciprocally regulate each other’s binding on active enhancers before and during adipogenesis. By focusing on enhancer activation by the adipogenic pioneer transcription factor C/EBPβ without inducing cell differentiation, we provide direct evidence for an interdependent relationship between BAF and MLL4 in activating cell type-specific enhancers. Together, these findings reveal a positive feedback between BAF and MLL4 in promoting LDTF-dependent activation of cell type-specific enhancers.

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Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Genes ◽

10.3390/genes12070968 ◽

2021 ◽

Vol 12 (7) ◽

pp. 968

Author(s):

Julien Van Gils ◽

Frederique Magdinier ◽

Patricia Fergelot ◽

Didier Lacombe

Keyword(s):

Chromatin Remodeling ◽

Developmental Disorder ◽

Facial Dysmorphism ◽

Diagnostic Efficiency ◽

Mendelian Disorders ◽

Pathogenic Variants ◽

Epigenetic Machinery ◽

Lysine Acetyltransferase ◽

Definition Of ◽

Crebbp Gene

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.

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