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PMID:22046413

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Citation

Dey, P, Ponnusamy, MP, Deb, S and Batra, SK (2011) Human RNA polymerase II-association factor 1 (hPaf1/PD2) regulates histone methylation and chromatin remodeling in pancreatic cancer. PLoS ONE 6:e26926

Abstract

Change in gene expression associated with pancreatic cancer could be attributed to the variation in histone posttranslational modifications leading to subsequent remodeling of the chromatin template during transcription. However, the interconnected network of molecules involved in regulating such processes remains elusive. hPaf1/PD2, a subunit of the human PAF-complex, involved in the regulation of transcriptional elongation has oncogenic potential. Our study explores the possibility that regulation of histone methylation by hPaf1 can contribute towards alteration in gene expression by nucleosomal rearrangement. Here, we show that knockdown of hPaf1/PD2 leads to decreased di- and tri-methylation at histone H3 lysine 4 residues in pancreatic cancer cells. Interestingly, hPaf1/PD2 colocalizes with MLL1 (Mixed Lineage Leukemia 1), a histone methyltransferase that methylates H3K4 residues. Also, a reduction in hPaf1 level resulted in reduced MLL1 expression and a corresponding decrease in the level of CHD1 (Chromohelicase DNA-binding protein 1), an ATPase dependent chromatin remodeling enzyme that specifically binds to H3K4 di and trimethyl marks. hPaf1/PD2 was also found to interact and colocalize with CHD1 in both cytoplasmic and nuclear extracts of pancreatic cancer cells. Further, reduced level of CHD1 localization in the nucleus in hPaf1/PD2 Knockdown cells could be rescued by ectopic expression of hPaf1/PD2. Micrococcal nuclease digestion showed an altered chromatin structure in hPaf1/PD2-KD cells. Overall, our results suggest that hPaf1/PD2 in association with MLL1 regulates methylation of H3K4 residues, as well as interacts and regulates nuclear shuttling of chromatin remodeling protein CHD1, facilitating its function in pancreatic cancer cells.

Links

PubMed PMC3203178 Online version:10.1371/journal.pone.0026926

Keywords

Chromatin Assembly and Disassembly; DNA Helicases/metabolism; DNA Helicases/physiology; DNA-Binding Proteins/metabolism; DNA-Binding Proteins/physiology; Gene Expression Regulation, Neoplastic; Histones/metabolism; Humans; Methylation; Myeloid-Lymphoid Leukemia Protein/metabolism; Myeloid-Lymphoid Leukemia Protein/physiology; Nuclear Proteins/physiology; Pancreatic Neoplasms/genetics; Pancreatic Neoplasms/pathology; RNA Polymerase II; Tumor Cells, Cultured

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PAF1

involved_in

GO:0016584: nucleosome positioning

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PAF1

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Fig. 2B, 5A

complete
CACAO 2705

HUMAN:PAF1

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Fig. 5A

complete
CACAO 2706

HUMAN:PAF1

GO:0031062: positive regulation of histone methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Fig. 1 and Fig. 2

complete
CACAO 2708

HUMAN:PAF1

GO:0034504: protein localization to nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Fig. 5AB

complete
CACAO 2710

HUMAN:PAF1

GO:0016584: nucleosome positioning

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Fig. 6

complete
CACAO 2711

HUMAN:PAF1

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Fig. 2A and Fig. 3AB and Fig. S1A

complete

HUMAN:PAF1

GO:0045727: positive regulation of translation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Fig. 2A and Fig. 3AB and Fig. S1A

complete

HUMAN:PAF1

GO:1900182: positive regulation of protein localization to nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Fig. 5AB; facilitates the localization of CHD1 to nucleus

complete

HUMAN:PAF1

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAF1

part_of

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAF1

involved_in

GO:0034504: protein localization to nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PAF1

involved_in

GO:0031062: positive regulation of histone methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CHD1

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CHD1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CHD1

GO:0005634: nucleus

ECO:0000314:

C

Fig. 5A

complete
CACAO 2702

HUMAN:CHD1

GO:0005737: cytoplasm

ECO:0000314:

C

Fig. 5A

complete
CACAO 2703

HUMAN:KMT2A

GO:0005634: nucleus

ECO:0000314:

C

Fig. 2B

complete
CACAO 2701

HUMAN:KMT2A

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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