title: HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci.
abstract: Cellular senescence is a stable cell growth arrest that is characterized by the silencing of proliferation-promoting genes through compaction of chromosomes into senescence-associated heterochromatin foci (SAHF). Paradoxically, senescence is also accompanied by increased transcription of certain genes encoding for secreted factors such as cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP). How SASP genes are excluded from SAHF-mediated global gene silencing remains unclear. In this study, we report that high mobility group box 2 (HMGB2) orchestrates the chromatin landscape of SASP gene loci. HMGB2 preferentially localizes to SASP gene loci during senescence. Loss of HMGB2 during senescence blunts SASP gene expression by allowing for spreading of repressive heterochromatin into SASP gene loci. This correlates with incorporation of SASP gene loci into SAHF. Our results establish HMGB2 as a novel master regulator that orchestrates SASP through prevention of heterochromatin spreading to allow for exclusion of SASP gene loci from a global heterochromatin environment during senescence.
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104.
authors: Katherine M
authors: http://orcid.org/0000-0002-5828-2325
authors: KM
authors: Aird
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104.
authors: Osamu
authors: O
authors: Iwasaki
authors: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104.
authors: Andrew V
authors: http://orcid.org/0000-0002-1536-0418
authors: AV
authors: Kossenkov
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104.
authors: Hideki
authors: http://orcid.org/0000-0002-2573-2473
authors: H
authors: Tanizawa
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104.|Kazan Federal University, Kazan 42000, Russia.
authors: Nail
authors: http://orcid.org/0000-0002-1235-395X
authors: N
authors: Fatkhutdinov
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104.
authors: Benjamin G
authors: BG
authors: Bitler
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104.|Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014.
authors: Linh
authors: http://orcid.org/0000-0001-9394-4761
authors: L
authors: Le
authors: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104.
authors: Gretchen
authors: http://orcid.org/0000-0001-8436-2890
authors: G
authors: Alicea
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014.
authors: Ting-Lin
authors: TL
authors: Yang
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014.
authors: F Brad
authors: http://orcid.org/0000-0003-4445-404X
authors: FB
authors: Johnson
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104.
authors: Ken-Ichi
authors: KI
authors: Noma
authors: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104 rzhang@wistar.org.
authors: Rugang
authors: R
authors: Zhang
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D005786:Gene Expression Regulation; D056426:Genetic Loci; D024261:HMGB2 Protein / Q000378:metabolism*; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D010641:Phenotype; D011485:Protein Binding; D055571:Secretory Pathway / Q000235:genetics
chemical_list: D002843:Chromatin; D024261:HMGB2 Protein; D006570:Heterochromatin