Unknown,Transcriptomics,Genomics,Proteomics

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Modulation of gene expression by ZNF143, THAP11 and NOTCH1 via overlapping binding sites in mammalian cells

ABSTRACT: In this study we investigated the genome wide DNA binding profile of ZNF143 and ICN1 in human and murine cells. We also analyzed the expression profile in human cells after overexpression or knockdown of ZNF143. To identify ZNF143 targets we performed ChIP-seq on 4 human cells lines and 3 murine cell types. We also identified, by ChIP-seq, ICN1 binding sites in HPB-ALL cells. To identify directly regulated genes by ZNF143, we analyzed, by RNA-seq, the expression profile after knockdown and overexpression of the transcription factor.

ORGANISM(S): Mus musculus

SUBMITTER: PHILIPPE CARBON

PROVIDER: E-GEOD-39263 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Modulation of gene expression via overlapping binding sites exerted by ZNF143, Notch1 and THAP11.

Ngondo-Mbongo Richard Patryk RP Myslinski Evelyne E Aster Jon C JC Carbon Philippe P

Nucleic acids research 20130213 7

ZNF143 is a zinc-finger protein involved in the transcriptional regulation of both coding and non-coding genes from polymerase II and III promoters. Our study deciphers the genome-wide regulatory role of ZNF143 in relation with the two previously unrelated transcription factors Notch1/ICN1 and thanatos-associated protein 11 (THAP11) in several human and murine cells. We show that two distinct motifs, SBS1 and SBS2, are associated to ZNF143-binding events in promoters of >3000 genes. Without co-o ...[more]

PMID: 23408857

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Project description:Recurrent mutations in histone modifying enzymes in multiple cancer types imply key roles in tumorigenesis. However, the functional relevance of these mutations remains unknown. Here we show that the JARID1B histone H3 lysine 4 demethylase is frequently amplified and overexpressed in luminal breast tumors and a somatic point mutation of JARID1B leads to the gain of luminal-specific gene expression programs. Downregulation of JARID1B in luminal breast cancer cells induces the expression of basal cell-specific genes and growth arrest, which is partially rescued by the inhibition of TGFBR thereby indicating a key role for TGFb signaling. Integrated genome-wide analysis of JARID1B chromatin binding, histone H3 lysine trimethyl (H3K4me3) and dimethyl (H3K4me2) patterns, and gene expression profiles in luminal and basal-like breast cancer cells suggest a key role for JARID1B in luminal cell-specific gene expression programs. A significant fraction of JARID1B binding-sites overlaps with CTCF in both luminal and basal-like breast cancer cells. CTCF also co-immunoprecipitates with JARID1B and it may influence its histone demethylase (HDM) activity as the H3K4me3/me2 ratio is lower at the CTCF-overlapping compared to JARID1B-unique sites. Additionally, a heterozygous JARID1B missense mutation (K1435R) in the HCC2157 basal-like breast cancer cell line is associated with unique JARID1B chromatin-binding and gene expression patterns implying gain of luminal features. In line with this, exogenous expression of this mutant in basal-like breast cancer cells leads to a gain of JARID1B binding at many luminal-specific genes. A PARADIGM score reflecting JARID1B activity in luminal breast cancer cells is associated with poor clinical outcome in patients with luminal breast tumors. Together, our data imply that JARID1B is a luminal lineage-driving oncogene and that its therapeutic targeting may represent a novel therapeutic strategy in treatment-resistant luminal breast tumors. RNA-Seq in breast cancer cell-lines transfected with JARID1B/CTCF/control siRNA. 50 cycles of sequencing on Illumina platform.

Dataset Information

Modulation of gene expression by ZNF143, THAP11 and NOTCH1 via overlapping binding sites in mammalian cells

Publications

Modulation of gene expression via overlapping binding sites exerted by ZNF143, Notch1 and THAP11.

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