Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging

Flex E1, Martinelli S2, Van Dijck A3, Ciolfi A4, Cecchetti S5, Coluzzi E6, Pannone L7, Andreoli C8, Radio FC4, Pizzi S4, Carpentieri G7, Bruselles A2, Catanzaro G9, Pedace L10, Miele E10, Carcarino E11, Ge X12, Chijiwa C13, Lewis MES13, Meuwissen M14, Kenis S15, Van der Aa N14, Larson A16, Brown K16, Wasserstein MP17, Skotko BG18, Begtrup A19, Person R19, Karayiorgou M20, Roos JL21, Van Gassen KL22, Koopmans M22, Bijlsma EK23, Santen GWE23, Barge-Schaapveld DQCM23, Ruivenkamp CAL23, Hoffer MJV23, Lalani SR24, Streff H24, Craigen WJ24, Graham BH25, van den Elzen APM26, Kamphuis DJ27, Õunap K28, Reinson K28, Pajusalu S29, Wojcik MH30, Viberti C31, Di Gaetano C31, Bertini E4, Petrucci S32, De Luca A33, Rota R10, Ferretti E34, Matullo G31, Dallapiccola B4, Sgura A6, Walkiewicz M35, Kooy RF36, Tartaglia M37

2019 Sep 5;105(3):493-508. doi: 10.1016/j.ajhg.2019.07.007. Epub 2019 Aug 22.

Author information

1

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy; Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

2

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy.

3

Department of Medical Genetics, University of Antwerp, Edegem, 2650 Belgium; Department of Neurology, Antwerp University Hospital, Edegem, 2650 Belgium.

4

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, 00146 Italy.

5

Microscopy Area, Core Facilities, Istituto Superiore di Sanità, Rome, 00161 Italy.

6

Department of Science, University Roma Tre, Rome, 00146 Italy.

7

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161 Italy; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, 00146 Italy.

8

Department of Environment and Health, Istituto Superiore di Sanità, Rome, 00161 Italy.

9

Department of Experimental Medicine, Sapienza University, Rome, 00161 Italy.

10

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146 Italy.

11

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146 Italy; Current affiliation: Cordeliers Research Centre, Inserm 1138, Sorbonne Université, Paris, 75006 France.

12

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Current affiliation: Department of Genetics and Genomic Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

13

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.

14

Department of Medical Genetics, University of Antwerp, Edegem, 2650 Belgium.

15

Department of Neurology, Antwerp University Hospital, Edegem, 2650 Belgium.

16

Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

17

Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA.

18

Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02114, USA.

19

GeneDx, Gaithersburg, MD 20877, USA.

20

Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA.

21

Department of Psychiatry, University of Pretoria, Weskoppies Hospital, Pretoria, 0001 South Africa.

22

Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, 3508 AB the Netherlands.

23

Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2300 RC the Netherlands.

24

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

25

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

26

Departement of Pediatrics, Reinier de Graaf Ziekenhuis, Delft, 2600 GA the Netherlands.

27

Departement of Neurology, Reinier de Graaf Ziekenhuis, Delft, 2600 GA the Netherlands.

28

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, 50406 Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, 50406 Estonia.

29

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, 50406 Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, 50406 Estonia; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.

30

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

31

Department of Medical Sciences, University of Turin, Turin, 10126 Italy; Italian Institute for Genomic Medicine, Turin, 10126 Italy.

32

Department of Clinical and Molecular Medicine, Sapienza University, Rome, 00189 Italy; Division of Medical Genetics, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, 71013 Italy.

33

Division of Medical Genetics, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, 71013 Italy.

34

Department of Experimental Medicine, Sapienza University, Rome, 00161 Italy; Istituto Neuromed, IRCCS, Pozzilli, 86077 Italy.

35

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Current affiliation: National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.

36

Department of Medical Genetics, University of Antwerp, Edegem, 2650 Belgium. Electronic address: frank.kooy@uantwerpen.be.

37

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, 00146 Italy. Electronic address: marco.tartaglia@opbg.net.

Abstract

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.