Drosophila NSD deletion induces developmental anomalies similar to those seen in Sotos syndrome 1 patients

다국어 초록 (Multilingual Abstract)

Background Haploinsufciency of the human nuclear receptor binding suppressor of variegation 3–9, enhancer of zeste, and trithorax (SET) domain 1 (NSD1) gene causes a developmental disorder called Sotos syndrome 1 (SOTOS1), which is associated with overgrowth and macrocephaly. NSD family proteins encoding histone H3 lysine 36 (H3K36) methyltransferases are conserved in many species, and Drosophila has a single NSD homolog gene, NSD.
Objective To gain insight into the biological functions of NSD1 defciency in the developmental anomalies seen in SOTOS1 patients using an NSD-deleted Drosophila mutant.
Methods We deleted Drosophila NSD using CRISPR/Cas9-mediated targeted gene knock-out, and analyzed pleiotropic phenotypes of the homozygous mutant of NSD (NSD−/−) at various developmental stages to understand the roles of NSD in Drosophila.
Results The site-specifc NSD deletion was confrmed in the mutant. The H3K36 di-methylation levels were dramatically decreased in the NSD−/− fy. Compared with the control, the NSD−/− fy displayed an increase in the body size of larvae, similar to the childhood overgrowth phenotype of SOTOS1 patients. Although the NSD mutant fies survived to adulthood, their fecundity was dramatically decreased. Furthermore, the NSD−/− fy showed neurological dysfunctions, such as lower memory performance and motor defects, and a diminished extracellular signal-regulated kinase (ERK) activity.
Conclusions The NSD-deleted Drosophila phenotype resembles many of the phenotypes of SOTOS1 patients, such as learning disability, deregulated ERK signaling, and overgrowth; thus, this mutant fy is a relevant model organism to study various SOTOS1 phenotypes.

참고문헌 (Reference)

1 Claudia Wellbrock, "V599EB-RAF is an Oncogene in Melanocytes" American Association for Cancer Research (AACR) 64 (64): 2338-2342, 2004

2 Agatino Battaglia, "Update on the clinical features and natural history of Wolf-Hirschhorn (4p-) syndrome: Experience with 87 patients and recommendations for routine health supervision" Wiley 148C (148C): 246-251, 2008

3 Eric J. Wagner, "Understanding the language of Lys36 methylation at histone H3" Springer Science and Business Media LLC 13 (13): 115-126, 2012

4 Nicola Dikow, "The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1 : Is it really a reversed sotos syndrome?" Wiley 161 (161): 2158-2166, 2013

5 Alison Foster, "The phenotype of Sotos syndrome in adulthood: A review of 44 individuals" Wiley 181 (181): 502-508, 2019

6 Daniel N. Weinberg, "The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape" Springer Science and Business Media LLC 573 (573): 281-286, 2019

7 Andreas Rechtsteiner, "The Histone H3K36 Methyltransferase MES-4 Acts Epigenetically to Transmit the Memory of Germline Gene Expression to Progeny" Public Library of Science (PLoS) 6 (6): e1001091-, 2010

8 P J Roberts, "Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer" Springer Science and Business Media LLC 26 (26): 3291-3310, 2007

9 M Rio, "Spectrum of NSD1 mutations in Sotos and Weaver syndromes" BMJ 40 (40): 436-440, 2003

10 T R Cole, "Sotos syndrome: a study of the diagnostic criteria and natural history." BMJ 31 (31): 20-32, 1994

11 Jessie McClelland, "Sotos syndrome: An unusual presentation with intrauterine growth restriction, generalized lymphedema, and intention tremor" Wiley 170 (170): 1064-1069, 2016

12 Naglaa M. Kamal, "Sotos syndrome" Ovid Technologies (Wolters Kluwer Health) 97 (97): e12867-, 2018

13 Katrina Tatton-Brown, "Sotos syndrome" Springer Science and Business Media LLC 15 (15): 264-271, 2007

14 Remco Visser, "Sotos Syndrome Is Associated with Deregulation of the MAPK/ERK-Signaling Pathway" Public Library of Science (PLoS) 7 (7): e49229-9, 2012

15 Karol Cichewicz, "ShinyR-DAM: a program analyzing Drosophila activity, sleep and circadian rhythms" Springer Science and Business Media LLC 1 (1): 25-, 2018

16 Swaminathan Venkatesh, "Set2 methylation of histone H3 lysine 36 suppresses histone exchange on transcribed genes" Springer Science and Business Media LLC 489 (489): 452-455, 2012

17 Daniel E. Martin-Herranz, "Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1" Springer Science and Business Media LLC 20 (20): 146-, 2019

18 Agda Karina Lucio-Eterovic, "Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function" Proceedings of the National Academy of Sciences 107 (107): 16952-16957, 2010

19 Han Zhang, "Reversed clinical phenotype due to a microduplication of Sotos syndrome region detected by array CGH: Microcephaly, developmental delay and delayed bone age" Wiley 155 (155): 1374-1378, 2011

20 Yuji Jeong, "Overexpression of histone methyltransferase NSD in Drosophila induces apoptotic cell death via the Jun-N-terminal kinase pathway" Elsevier BV 496 (496): 1134-1140, 2018

21 Taejoon Kim, "Overexpression of H3K36 methyltransferase NSD in glial cells affects brain development in Drosophila" Wiley 68 (68): 2503-2516, 2020

22 Wang GG, "NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis" 9 : 804-812, 2007

23 G. V. Rayasam, "NSD1 is essential for early post-implantation development and has a catalytically active SET domain" Wiley 22 (22): 3153-3163, 2003

24 Darrel J. Waggoner, "NSD1 analysis for Sotos syndrome: Insights and perspectives from the clinical laboratory" Elsevier BV 7 (7): 524-533, 2005

25 Jenny Douglas, "NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes" Elsevier BV 72 (72): 132-143, 2003

26 Armelle Luscan, "Mutations inSETD2cause a novel overgrowth condition" BMJ 51 (51): 512-517, 2014

27 Seval Türkmen, "Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes" Springer Science and Business Media LLC 11 (11): 858-865, 2003

28 Laurel B. Bender, "MES-4: an autosome-associated histone methyltransferase that participates in silencing the X chromosomes in theC. elegansgerm line" The Company of Biologists 133 (133): 3907-3917, 2006

29 Oliver Bell, "Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila" Wiley 26 (26): 4974-4984, 2007

30 Lily Kahsai, "Learning and Memory in Drosophila: Behavior, Genetics, and Neural Systems" Elsevier 99 : 139-167, 2011

31 Sabrina Oishi, "Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1" Wiley 19 (19): e12637-, 2020

32 Capowski EE, "Identifcation of grandchildless loci whose products are required for normal germline development in the nematode Caenorhabditis elegans" 129 : 1061-1072, 1991

33 Shota Suzuki, "Histone H3K36 trimethylation is essential for multiple silencing mechanisms in fission yeast" Oxford University Press (OUP) 44 (44): 4147-4162, 2016

34 Naohiro Kurotaki, "Haploinsufficiency of NSD1 causes Sotos syndrome" Springer Science and Business Media LLC 30 (30): 365-366, 2002

35 Stephen L. McDaniel, "H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity" Elsevier BV 19 (19): 2371-2382, 2017

36 Katrina Tatton-Brown, "Genotype-Phenotype Associations in Sotos Syndrome: An Analysis of 266 Individuals with NSD1 Aberrations" Elsevier BV 77 (77): 193-204, 2005

37 Scott J Gratz, "Genome Engineering of Drosophila with the CRISPR RNA-Guided Cas9 Nuclease" Oxford University Press (OUP) 194 (194): 1029-1035, 2013

38 Anna M. Migdalska, "Generation of the Sotos syndrome deletion in mice" Springer Science and Business Media LLC 23 (23): 749-757, 2012

39 Beverley B Matthews, "Gene Model Annotations for Drosophila melanogaster: Impact of High-Throughput Data" Oxford University Press (OUP) 5 (5): 1721-1736, 2015

40 J.A. Rosenfeld, "Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly" S. Karger AG 3 : 247-254, 2013

41 Aoife Larkin, "FlyBase: updates to the Drosophila melanogaster knowledge base" Oxford University Press (OUP) 49 (49): D899-D907, 2021

42 Park SH, "First identifed Korean family with Sotos syndrome caused by a novel intragenic mutation in NSD1" 44 : 228-231, 2014

43 Lenan Zhuang, "Depletion of Nsd2-mediated histone H3K36 methylation impairs adipose tissue development and function" Springer Science and Business Media LLC 9 (9): 1796-, 2018

44 Young Bae Sohn, "Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations" Springer Science and Business Media LLC 58 (58): 73-77, 2013

45 Juan F. Sotos, "Cerebral Gigantism in Childhood" Massachusetts Medical Society 271 (271): 109-116, 1964

46 Shuhua Zhang, "CRISPR/Cas9-mediated knockout of NSD1 suppresses the hepatocellular carcinoma development via the NSD1/H3/Wnt10b signaling pathway" Springer Science and Business Media LLC 38 (38): 467-, 2019

47 A. Righini, "Brain Magnetic Resonance Imaging in Wolf-Hirschhorn Syndrome" Georg Thieme Verlag KG 38 (38): 25-28, 2007

48 Matthew R. Fickie, "Adults with Sotos syndrome: Review of 21 adults with molecularly confirmed NSD1 alterations, including a detailed case report of the oldest person" Wiley 155 (155): 2105-2111, 2011

49 Daphne S. Cabianca, "Active chromatin marks drive spatial sequestration of heterochromatin in C. elegans nuclei" Springer Science and Business Media LLC 569 (569): 734-739, 2019

50 Luis M Franco, "A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion" Springer Science and Business Media LLC 18 (18): 258-261, 2010

51 Salinee Jantrapirom, "A new Drosophila model of Ubiquilin knockdown shows the effect of impaired proteostasis on locomotive and learning abilities" Elsevier BV 362 (362): 461-471, 2018