Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

ABSTRACT: Mice with colonic tumors (chemically induced by AOM/DSS) were treated with Nutlin or control vehicle solution to analyze p53 target gene expression in vivo.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Florian Wegwitz

PROVIDER: E-MTAB-10041 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity.

Isermann Tamara T Şener Özge Çiçek ÖÇ Stender Adrian A Klemke Luisa L Winkler Nadine N Neesse Albrecht A Li Jinyu J Wegwitz Florian F Moll Ute M UM Schulz-Heddergott Ramona R

Nature communications 20210629 1

The vast majority of human tumors with p53 mutations undergo loss of the remaining wildtype p53 allele (loss-of-heterozygosity, p53LOH). p53LOH has watershed significance in promoting tumor progression. However, driving forces for p53LOH are poorly understood. Here we identify the repressive WTp53-HSF1 axis as one driver of p53LOH. We find that the WTp53 allele in AOM/DSS chemically-induced colorectal tumors (CRC) of p53<sup>R248Q/+</sup> mice retains partial activity and represses heat-shock fa ...[more]

PMID: 34188043

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Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.

Dataset Information

RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Publications

Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity.

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