Role of ATRX Chromatin Remodelling Factor in α‐Thalassaemia X‐Linked Mental Retardation

Abstract

α‐Thalassaemia X‐linked mental retardation (ATR‐X syndrome) is a congenital disorder typified by intellectual disability, abnormalities in growth and genital formation, and mild anaemia. Mutations resulting in the reduced function of the ATRX chromatin remodelling protein underlie these symptoms. Variability in the severity of disease characteristics may be associated either with mutations that affect different regions of ATRX or with individual variability in the chromosome landscape targeted by it. ATRX associates with proteins involved in regulating chromatin structure and repression of gene expression in repetitive, transcriptionally silent regions of the genome. Loss of ATRX function can be associated with altered gene expression, including reduced α‐globin expression; impairment in DNA repair; and the maintenance of chromosome stability, which may most critically affect normal development within tissues such as the brain and testes. The current standard of care for ATR‐X syndrome focuses on the management of symptoms, with targeted therapeutics lacking.

Key Concepts

  • ATR‐X syndrome is caused by loss‐of‐function mutations that result in the diminished expression, or reduced functionality, of the ATRX protein.
  • Though clinical features of ATR‐X syndrome show variability, common characteristics include facial dysmorphism, stunted growth, hypotonia, microcephaly, intellectual disability, mild anaemia with detectable haemoglobin H (HbH) and genital abnormalities.
  • ATR‐X syndrome is a nonprogressive disorder, involving abnormal development.
  • ATRX is a widely expressed chromatin remodelling protein, whose function affects both genomic stability and gene expression.
  • The histone chaperone complex formed by DAXX and ATRX is critical for loading the histone variant H3.3 onto chromatin.
  • The function of ATRX may be most critical during the rapid expansion of cells that occurs during development within particular organs, such as the expansion of cortical neurons in the brain or Sertoli cells in the testes.

Keywords: ATR‐X syndrome; intellectual disability; HbH; neurodevelopmental disorder; SWI/SNF; histone H3.3; DAXX; HP1α/β; epigenetics; chromatin remodelling

Figure 1. Domain structure of ATRX. Two key domains, highly conserved within mammals, exist in ATRX. The N‐terminal ADD domain contains a PHD‐type zinc finger and is involved in histone 3 binding, heterochromatin maintenance and transcriptional repression. The C‐terminal SWI/SNF domain contains an ATPase domain and helicase domain repeats (black bars) and is involved in DNA recombination and repair, histone exchange and maintenance of heterochromatin. The bottom portion of the figure shows the amino acid similarity between human and mouse proteins.Adapted from Picketts et al.1998 © Springer.
Figure 2. ATRX complexes with multiple proteins to affect nucleosome structure at unique chromatin sites and participates in DNA repair. (a) ATRX interacts with DAXX, HP1α, MeCP2 and histone 3.3 at G‐rich and repetitive chromatin regions to maintain transcriptional silencing. ATRX and HP1α localise to telomeres in mouse ES cells, dependent upon an interaction with H3.3. HP1α binds to H3K9me3, and may help guide ATRX to certain target regions. ATRX helps to maintain the H3K9me3 modification, primarily within heterochromatin. DAXX envelopes H3.3, acting as a specific chaperone for this histone. Incorporation of H3.3 is mutually exclusive with the incorporation of mH2A. The ATRX interaction with histone 3 is through its ADD domain, which may also interact with double‐stranded DNA. ATRX interacts with DAXX and MeCP2 through its C‐terminal SWI/SNF helicase domain. MeCP2 may aid in ATRX localising to methylated DNA. (b) ATRX localises with SETDB1, TRIM28 and ZNF274 at 3′ zinc finger protein gene exons, in association with H3K9me3 and H3K36me3, to maintain chromatin stability at these loci. (c) ATRX is a binding partner of Mre11‐Rad50‐Nbs1 (MRN) complex. Its interaction with this complex facilitates DNA replication during S and G2 phases and prevents replication fork stalling.
close

References

Abidi FE, Cardoso C, Lossi A‐M, et al. (2005) Mutation in the 5[prime] alternatively spliced region of the XNP//ATR‐X gene causes Chudley‐Lowry syndrome. European Journal of Human Genetics 13 (2): 176–183.

Argentaro A, Yang J‐C, Chapman L, et al. (2007) Structural consequences of disease‐causing mutations in the ATRX‐DNMT3‐DNMT3L (ADD) domain of the chromatin‐associated protein ATRX. Proceedings of the National Academy of Sciences of the United States of America 104 (29): 11939–11944.

Badens C, Lacoste C, Philip N, et al. (2006) Mutations in PHD‐like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome. Clinical Genetics 70 (1): 57–62.

Bagheri‐Fam S, Argentaro A, Svingen T, et al. (2011) Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR‐X syndrome. Human Molecular Genetics 20 (11): 2213–2224.

Basehore MJ, Michaelson‐Cohen R, Levy‐Lahad E, et al. (2015) Alpha‐thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation – c.109C > T (p.R37X). Clinical Genetics 87 (5): 461–466.

Berry‐Kravis E, Des Portes V, Hagerman R, et al. (2016) Mavoglurant in fragile X syndrome: results of two randomized, double‐blind, placebo‐controlled trials. Science Translational Medicine 8 (321): 321ra5.

Bérubé NG, Mangelsdorf M, Jagla M, et al. (2005) The chromatin‐remodeling protein ATRX is critical for neuronal survival during corticogenesis. Journal of Clinical Investigation 115 (2): 258–267.

Carmichael ST (2016) Emergent properties of neural repair: elemental biology to therapeutic concepts. Annals of Neurology 79 (6): 895–906.

Clynes D, Jelinska C, Xella B, et al. (2014) ATRX dysfunction induces replication defects in primary mouse cells. PLoS One 9 (3): e92915.

Craddock CF, Vyas P, Sharpe JA, et al. (1995) Contrasting effects of alpha and beta globin regulatory elements on chromatin structure may be related to their different chromosomal environments. EMBO Journal 14 (8): 1718–1726.

Devlin AM, Cross JH, Harkness W, et al. (2003) Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 126 (3): 556–566.

Dhayalan A, Tamas R, Bock I, et al. (2011) The ATRX‐ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9. Human Molecular Genetics 20 (11): 2195–2203.

Elsasser SJ, Huang H, Lewis PW, et al. (2012) DAXX envelops a histone H3.3‐H4 dimer for H3.3‐specific recognition. Nature 491 (7425): 560–565.

Garrick D, Sharpe JA, Arkell R, et al. (2006) Loss of Atrx affects trophoblast development and the pattern of X‐inactivation in extraembryonic tissues. PLoS Genetics 2 (4): e58.

Giardine B, Borg J, Higgs D, et al. (2011) Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. Nature Genetics 43 (4): 295–302.

Gibbons RJ, Wilkie AO, Weatherall DJ, et al. (1991) A newly defined X linked mental retardation syndrome associated with alpha thalassaemia. Journal of Medical Genetics 28 (11): 729–733.

Gibbons RJ, Picketts DJ, Villard L, et al. (1995) Mutations in a putative global transcriptional regulator cause X‐linked mental retardation with α‐thalassemia (ATR‐X syndrome). Cell 80 (6): 837–845.

Gibbons RJ, Bachoo S, Picketts DJ, et al. (1997) Mutations in transcriptional regulator ATRX establish the functional significance of a PHD‐like domain. Nature Genetics 17 (2): 146–148.

Gibbons R (2006) Alpha thalassaemia‐mental retardation, X linked. Orphanet Journal of Rare Diseases 1 (1): 1–9.

Gibbons RJ, Wada T, Fisher CA, et al. (2008) Mutations in the chromatin‐associated protein ATRX. Human Mutation 29 (6): 796–802.

Gibbons RJ (2012) α‐Thalassemia, mental retardation, and myelodysplastic syndrome. Cold Spring Harbor Perspectives in Medicine 2 (10: pii: a011759).

Gogliotti RG, Senter RK, Rook JM, et al. (2016) mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome. Human Molecular Genetics. DOI: 10.1093/hmg/ddw074.

Grozeva D, Carss K, Spasic‐Boskovic O, et al. (2015) Targeted next‐generation sequencing analysis of 1,000 individuals with intellectual disability. Human Mutation 36 (12): 1197–1204.

He Q, Kim H, Huang R, et al. (2015) The Daxx/Atrx complex protects tandem repetitive elements during DNA hypomethylation by promoting H3K9 trimethylation. Cell Stem Cell 17 (3): 273–286.

Huh MS, Price O'Dea T, Ouazia D, et al. (2012) Compromised genomic integrity impedes muscle growth after Atrx inactivation. Journal of Clinical Investigation 122 (12): 4412–4423.

Huh MS, Ivanochko D, Hashem LE, et al. (2016) Stalled replication forks within heterochromatin require ATRX for protection. Cell Death & Disease 7: e2220.

Iwase S, Xiang B, Ghosh S, et al. (2011) ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental‐retardation syndrome. Nature Structural and Molecular Biology 18 (7): 769–776.

Knight SJL (2001) Intellectual Disability: Genetics (In eLS). Chichester: John Wiley & Sons, Ltd.

Law MJ, Lower KM, Voon HPJ, et al. (2010) ATR‐X syndrome protein targets tandem repeats and influences allele‐specific expression in a size‐dependent manner. Cell 143 (3): 367–378.

Leung JW‐C, Ghosal G, Wang W, et al. (2013) Alpha thalassemia/mental retardation syndrome X‐linked gene product ATRX is required for proper replication restart and cellular resistance to replication stress. Journal of Biological Chemistry 288 (9): 6342–6350.

Levy MA, Kernohan KD, Jiang Y, et al. (2015) ATRX promotes gene expression by facilitating transcriptional elongation through guanine‐rich coding regions. Human Molecular Genetics 24 (7): 1824–1835.

McPherson EW, Clemens MM, Gibbons RJ, et al. (1995) X‐linked α‐thalassemia/mental retardation (ATR‐X) syndrome: a new kindred with severe genital anomalies and mild hematologic expression. American Journal of Medical Genetics 55 (3): 302–306.

Nogami T, Beppu H, Tokoro T, et al. (2011) Reduced expression of the ATRX gene, a chromatin‐remodeling factor, causes hippocampal dysfunction in mice. Hippocampus 21 (6): 678–687.

Noh K‐M, Maze I, Zhao D, et al. (2015) ATRX tolerates activity‐dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons. Proceedings of the National Academy of Sciences of the United States of America 112 (22): 6820–6827.

Picketts DJ, Higgs DR, Bachoo S, et al. (1996) ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR‐X syndrome. Human Molecular Genetics 5 (12): 1899–1907.

Picketts DJ, Tastan AO, Higgs DR, et al. (1998) Comparison of the human and murine ATRX gene identifies highly conserved, functionally important domains. Mammalian Genome 9 (5): 400–403.

Ratnakumar K, Duarte LF, LeRoy G, et al. (2012) ATRX‐mediated chromatin association of histone variant macroH2A1 regulates α‐globin expression. Genes & Development 26 (5): 433–438.

Sadic D, Schmidt K, Groh S, et al. (2015) Atrx promotes heterochromatin formation at retrotransposons. EMBO Reports 16 (7): 836–850.

Shioda N, Beppu H, Fukuda T, et al. (2011) Aberrant calcium/calmodulin‐dependent protein kinase II (CaMKII) activity is associated with abnormal dendritic spine morphology in the ATRX mutant mouse brain. Journal of Neuroscience 31 (1): 346–358.

Stevenson RE and Schwartz CE (2009) X‐linked intellectual disability: unique vulnerability of the male genome. Developmental Disabilities Research Reviews 15 (4): 361–368.

Udugama M, Chang FT, Chan FL, et al. (2015) Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri‐methylation mark at telomeres. Nucleic Acids Research 43 (21): 10227–10237.

Valle‐García D, Qadeer ZA, McHugh DS, et al. (2016) ATRX binds to atypical chromatin domains at the 3′ exons of zinc finger genes to preserve H3K9me3 enrichment. Epigenetics 11 (6): 398–414.

Villard L, Toutain A, Lossi AM, et al. (1996) Splicing mutation in the ATR‐X gene can lead to a dysmorphic mental retardation phenotype without alpha‐thalassemia. American Journal of Human Genetics 58 (3): 499–505.

Voon HPJ, Hughes Jim R, Rode C, et al. (2015) ATRX plays a key role in maintaining silencing at interstitial heterochromatic loci and imprinted genes. Cell Reports 11 (3): 405–418.

Voon HPJ and Wong LH (2016) New players in heterochromatin silencing: histone variant H3.3 and the ATRX/DAXX chaperone. Nucleic Acids Research 44 (4): 1496–1501.

Wada T, Ban H, Matsufuji M, et al. (2013) Neuroradiologic features in X‐linked α‐thalassemia/mental retardation syndrome. American Journal of Neuroradiology 34 (10): 2034–2038.

Weatherall DJ, Higgs DR, Bunch C, et al. (1981) Hemoglobin H disease and mental retardation. New England Journal of Medicine 305 (11): 607–612.

Wilkie AO, Zeitlin HC, Lindenbaum RH, et al. (1990a) Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the alpha globin complex. American Journal of Human Genetics 46 (6): 1127–1140.

Wilkie AOM, Buckle VJ, Harris PC, et al. (1990b) Clinical features and molecular analysis of the α thalassemia/mental retardation syndromes. 1. Cases due to deletions involving chromosome band 16p13.3. American Journal of Human Genetics 46 (6): 1112–1126.

Xue Y, Gibbons R, Yan Z, et al. (2003) The ATRX syndrome protein forms a chromatin‐remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies. Proceedings of the National Academy of Sciences of the United States of America 100 (19): 10635–10640.

Further Reading

Elsässer SJ, Allis CD and Lewis PW (2011) New epigenetic drivers of cancers. Science 331 (6021): 1145–1146.

Kleefstra T, Schenck A, Kramer JM, et al. (2014) The genetics of cognitive epigenetics. Neuropharmacology 80: 83–94.

Millan MJ (2013) An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy. Neuropharmacology 68: 2–82.

Ritchie K, Watson LA, Davidson B, et al. (2014) ATRX is required for maintenance of the neuroprogenitor cell pool in the embryonic mouse brain. Biology Open 3 (12): 1158–1163.

Urdinguio RG, Sanchez‐Mut JV and Esteller M (2009) Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet. Neurology 8 (11): 1056–1072.

Watson LA, Goldberg H and Bérubé NG (2015) Emerging roles of ATRX in cancer. Epigenomics 7 (8): 1365–1378.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Young, Kevin G, and Picketts, David J(Nov 2016) Role of ATRX Chromatin Remodelling Factor in α‐Thalassaemia X‐Linked Mental Retardation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026558]