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Cell Discov. 2016 Dec 6;2:16045. eCollection 2016.

HnRNPA2 is a novel histone acetyltransferase that mediates mitochondrial stress-induced nuclear gene expression.

Author information

1
Department of Biomedical Sciences & Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.
2
Department of Pharmacological Sciences, Stony Brook University , Stony Brook, NY, USA.
3
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
4
Penn Vet Imaging Core, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.
5
Vascular Medicine Institute, University of Pittsburg , Pittsburgh, PA, USA.
6
Nucleic Acid/Protein Core Facility, Children's Hospital of Philadelphia Research Institute , Philadelphia, PA, USA.
7
Histopathology Facility, Fox Chase Cancer Center, Temple University , Philadelphia, PA, USA.
8
Department of Gastroenterology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
9
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur , Bangalore, India.

Abstract

Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced transcription coactivator hnRNAP2 acetylates Lys 8 of H4 through an intrinsic histone lysine acetyltransferase (KAT) activity with Arg 48 and Arg 50 of hnRNAP2 being essential for acetyl-CoA binding and acetyltransferase activity. H4K8 acetylation at the mitochondrial stress-responsive promoters by hnRNAP2 is essential for transcriptional activation. We found that the previously described mitochondria-to-nucleus retrograde signaling-mediated transformation of C2C12 cells caused an increased expression of genes involved in various oncogenic processes, which is retarded in hnRNAP2 silenced or hnRNAP2 KAT mutant cells. Taken together, these data show that altered gene expression by mitochondria-to-nucleus retrograde signaling involves a novel hnRNAP2-dependent epigenetic mechanism that may have a role in cancer and other pathologies.

KEYWORDS:

Mitochondrial retrograde signaling (MtRS); acetyl-CoA binding domain; histone acetylation; hnRNPA2; mtDNA depletion; telomerase activation; transcriptional coactivator

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