HnRNPA2 is a Novel Histone Acetyltransferase That Mediates Mitochondrial Stress-Induced Nuclear Gene Expression

Authors

Manti Guha, University of Pennsylvania
Satish Srinivasan, University of Pennsylvania
Kip Guja, Stony Brook University
Edison Mejia, Stony Brook University
Miguel Garcia-Diaz, Stony Brook University
F. Brad Johnson, University of Pennsylvania
Gordon Ruthel, University of Pennsylvania
Brett A. Kaufman, University of Pittsburg
Eric F. Rappaport, Children’s Hospital of Philadelphia Research Institute
M. Rebecca Glineburg, Chapman UniversityFollow
Ji-Kang Fang, University of Pennsylvania
Andres J. Klein-Szanto, Temple University
Hiroshi Nakagawa, University of Pennsylvania
Jeelan Basha, Jawaharlal Nehru Centre for Advanced Scientific Research
Tapas Kundu, Jawaharlal Nehru Centre for Advanced Scientific Research
Narayan G. Avadhani, University of Pennsylvania

Document Type

Article

Publication Date

12-6-2016

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.

Comments

This article was originally published in Cell Discovery, volume 2, in 2016. https://doi.org/10.1038/celldisc.2016.45

Recommended Citation

Guha M, Srinivasan S, Guja K, Mejia E, Garcia-Diaz M, Johnson FB, Ruthel G, Kaufman BA, Rappaport EF, Glineburg MR, Fang JK, Szanto AK, Nakagawa H, Basha J, Kundu T, Avadhani NG., “HnRNPA2 is a novel histone acetyltransferase that mediates mitochondrial stress-induced nuclear gene expression.” Cell Discov. 2016 Dec 6;2:16045. https://doi.org/10.1038/celldisc.2016.45

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The authors

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This work is licensed under a Creative Commons Attribution 4.0 License.