Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Whole genome expression data comparison between WT and Cebpg-/- MEFs.

ABSTRACT: C/EBPÎ² is an important regulator of oncogene-induced senescence (OIS). Here we show that C/EBPÎ³, a heterodimeric partner of C/EBPÎ² whose biological functions are not well understood, inhibits cellular senescence. Cebpg-/- MEFs proliferated poorly, entered senescence prematurely, and expressed a pro-inflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBPÎ². The senescence-suppressing activity of C/EBPÎ³ required its ability to heterodimerize with C/EBPÎ². Covalently linked C/EBPÎ² homodimers (Î²~Î²) inhibited the proliferation and tumorigenicity of RasV12-transformed NIH3T3 cells, activated SASP gene expression, and recruited the CBP co-activator in a Ras-dependent manner, whereas Î³~Î² heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg-/- MEFs. C/EBPÎ² depletion partially restored growth of C/EBPÎ³-deficient cells, indicating that the increased levels of C/EBPÎ² homodimers in Cebpg-/- MEFs inhibit proliferation. The proliferative functions of C/EBPÎ³ are not restricted to fibroblasts, as hematopoietic progenitors from Cebpg-/- bone marrow also displayed impaired growth. Furthermore, high CEBPG expression correlated with poorer clinical prognoses in several human cancers, and C/EBPÎ³ depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBPÎ³ neutralizes the cytostatic activity of C/EBPÎ² through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes. Mouse embryonic fibroblasts were isolated at E13.5 and propagated. At passage 3 cells were plated with equal density and collected 48 hours later.

ORGANISM(S): Mus musculus

SUBMITTER: Peter Johnson

PROVIDER: E-GEOD-47777 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

C/EBPγ suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBPβ.

Huggins Christopher J CJ Malik Radek R Lee Sook S Salotti Jacqueline J Thomas Sara S Martin Nancy N Quiñones Octavio A OA Alvord W Gregory WG Olanich Mary E ME Keller Jonathan R JR Johnson Peter F PF

Molecular and cellular biology 20130617 16

C/EBPβ is an important regulator of oncogene-induced senescence (OIS). Here, we show that C/EBPγ, a heterodimeric partner of C/EBPβ whose biological functions are not well understood, inhibits cellular senescence. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferated poorly, entered senescence prematurely, and expressed a proinflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBPβ. Th ...[more]

PMID: 23775115

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Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces Ã¢Â?Â?SASP-likeÃ¢Â?Â? inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study examines the genome-wide distribution of gH2A.x and H3K4me3 by chIP-seq, using input and whole histone subunit H3 (respectively) as controls for local sonication efficiency bias. Each of the four chIPs has a single replicate each in (i) IMR90 fibroblasts transfected with a scramble control vector, (ii) the same cells subject to oncogene-induced senescence by stimulation of H-Ras V12, and (iii) in OIS cells with a shRNA targeting MLL1. Additionally, gH2A.x and input were sequenced with another replicate in control and OIS cells (both scramble control).

Dataset Information

Whole genome expression data comparison between WT and Cebpg-/- MEFs.

Publications

C/EBPγ suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBPβ.

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