title: HDAC1 and HDAC2 collectively regulate intestinal stem cell homeostasis.
abstract: Histone deacetylases (HDACs) are posttranslational modifiers that deacetylate proteins. Despite their crucial role in numerous biological processes, the use of broad-range HDAC inhibitors (HDACi), has shown clinical efficacy. However, undesired side effects highlight the necessity to better understand the biology of different HDACs and target the relevant HDACs. Using a novel mouse model, in which HDAC1 and HDAC2 can be simultaneously deleted in the intestine of adult mice, we show that the simultaneous deletion of HDAC1 and HDAC2 leads to a rapid loss of intestinal homeostasis. Importantly, this deletion cannot be sustained, and 8 days after initial ablation, stem cells that have escaped HDAC1 or HDAC2 deletion swiftly repopulate the intestinal lining. In vitro ablation of HDAC1 and HDAC2 using intestinal organoid cultures resulted in a down-regulation of multiple intestinal stem cell markers and functional loss of clonogenic capacity. Importantly, treatment of wild-type organoids with class I-specific HDACi MS-275 also induced a similar loss of stemness, providing a possible rationale for the gastrointestinal side effects often observed in HDACi-treated patients. In conclusion, these data show that HDAC1 and HDAC2 have a redundant function and are essential to maintain intestinal homeostasis.
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Cheryl D
authors: CD
authors: Zimberlin
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Cesare
authors: C
authors: Lancini
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Rachel
authors: R
authors: Sno
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Sanne L
authors: SL
authors: Rosekrans
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Chelsea M
authors: CM
authors: McLean
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Hanneke
authors: H
authors: Vlaming
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Gijs R
authors: GR
authors: van den Brink
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Michael
authors: M
authors: Bots
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands.
authors: Jan Paul
authors: JP
authors: Medema
authors: *Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and Cancer Genomics Center, Utrecht, The Netherlands j.dannenberg@nki.nl.
authors: Jan-Hermen
authors: JH
authors: Dannenberg
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007422:Intestines / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology
chemical_list: D001549:Benzamides; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; C118739:entinostat; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: MS-275; histone deacetylase; histone deacetylase inhibitor; organoids