title: HnRNPA2 is a novel histone acetyltransferase that mediates mitochondrial stress-induced nuclear gene expression.
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.
authors.affiliation: Department of Biomedical Sciences & Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Manti
authors.initials: M
authors.lastname: Guha
authors.affiliation: Department of Biomedical Sciences & Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University , Stony Brook, NY, USA.
authors.forename: Kip
authors.initials: K
authors.lastname: Guja
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University , Stony Brook, NY, USA.
authors.forename: Edison
authors.initials: E
authors.lastname: Mejia
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University , Stony Brook, NY, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia-Diaz
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: F Brad
authors.initials: FB
authors.lastname: Johnson
authors.affiliation: Penn Vet Imaging Core, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.affiliation: Vascular Medicine Institute, University of Pittsburg , Pittsburgh, PA, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Kaufman
authors.affiliation: Nucleic Acid/Protein Core Facility, Children's Hospital of Philadelphia Research Institute , Philadelphia, PA, USA.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rappaport
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: M Rebecca
authors.initials: MR
authors.lastname: Glineburg
authors.affiliation: Department of Biomedical Sciences & Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Ji-Kang
authors.initials: JK
authors.lastname: Fang
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.affiliation: Histopathology Facility, Fox Chase Cancer Center, Temple University , Philadelphia, PA, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Klein Szanto
authors.affiliation: Department of Gastroenterology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur , Bangalore, India.
authors.forename: Jeelan
authors.initials: J
authors.lastname: Basha
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur , Bangalore, India.
authors.forename: Tapas
authors.initials: T
authors.lastname: Kundu
authors.affiliation: Department of Biomedical Sciences & Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Narayan G
authors.initials: NG
authors.lastname: Avadhani
keywords: Mitochondrial retrograde signaling (MtRS); acetyl-CoA binding domain; histone acetylation; hnRNPA2; mtDNA depletion; telomerase activation; transcriptional coactivator