Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYNSNNZ)

• DOT Name: KAT8 regulatory NSL complex subunit 1 (KANSL1)
• Synonyms: MLL1/MLL complex subunit KANSL1; MSL1 homolog 1; hMSL1v1; NSL complex protein NSL1; Non-specific lethal 1 homolog
• Gene Name: KANSL1
• Related Disease:
  Koolen-de Vries syndrome
  Advanced cancer
  Breast carcinoma
  Cardiofaciocutaneous syndrome
  Epilepsy
  Leiomyoma
  Major depressive disorder
  Mood disorder
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Primary biliary cholangitis
  Trichohepatoenteric syndrome
  Koolen-de Vries syndrome due to a point mutation
  Androgenetic alopecia
  Baldness, male pattern
  Intellectual disability
  Parkinson disease
  Uterine fibroids
• UniProt ID: KANL1_HUMAN
• PDB ID: 4CY1; 4CY2
• Pfam ID: PF15275
• Sequence:
  MAAMAPALTDAAAEAHHIRFKLAPPSSTLSPGSAENNGNANILIAANGTKRKAIAAEDPS
  LDFRNNPTKEDLGKLQPLVASYLCSDVTSVPSKESLKLQGVFSKQTVLKSHPLLSQSYEL
  RAELLGRQPVLEFSLENLRTMNTSGQTALPQAPVNGLAKKLTKSSTHSDHDNSTSLNGGK
  RALTSSALHGGEMGGSESGDLKGGMTNCTLPHRSLDVEHTTLYSNNSTANKSSVNSMEQP
  ALQGSSRLSPGTDSSSNLGGVKLEGKKSPLSSILFSALDSDTRITALLRRQADIESRARR
  LQKRLQVVQAKQVERHIQHQLGGFLEKTLSKLPNLESLRPRSQLMLTRKAEAALRKAASE
  TTTSEGLSNFLKSNSISEELERFTASGIANLRCSEQAFDSDVTDSSSGGESDIEEEELTR
  ADPEQRHVPLRRRSEWKWAADRAAIVSRWNWLQAHVSDLEYRIRQQTDIYKQIRANKGLI
  VLGEVPPPEHTTDLFLPLSSEVKTDHGTDKLIESVSQPLENHGAPIIGHISESLSTKSCG
  ALRPVNGVINTLQPVLADHIPGDSSDAEEQLHKKQRLNLVSSSSDGTCVAARTRPVLSCK
  KRRLVRPNSIVPLSKKVHRNSTIRPGCDVNPSCALCGSGSINTMPPEIHYEAPLLERLSQ
  LDSCVHPVLAFPDDVPTSLHFQSMLKSQWQNKPFDKIKPPKKLSLKHRAPMPGSLPDSAR
  KDRHKLVSSFLTTAKLSHHQTRPDRTHRQHLDDVGAVPMVERVTAPKAERLLNPPPPVHD
  PNHSKMRLRDHSSERSEVLKHHTDMSSSSYLAATHHPPHSPLVRQLSTSSDSPAPASSSS
  QVTASTSQQPVRRRRGESSFDINNIVIPMSVAATTRVEKLQYKEILTPSWREVDLQSLKG
  SPDEENEEIEDLSDAAFAALHAKCEEMERARWLWTTSVPPQRRGSRSYRSSDGRTTPQLG
  SANPSTPQPASPDVSSSHSLSEYSHGQSPRSPISPELHSAPLTPVARDTPRHLASEDTRC
  STPELGLDEQSVQPWERRTFPLAHSPQAECEDQLDAQERAARCTRRTSGSKTGRETEAAP
  TSPPIVPLKSRHLVAAATAQRPTHR
• Function: As part of the NSL complex it is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription.
• Tissue Specificity: Expressed in the brain.
• Reactome Pathway:
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Koolen-de Vries syndrome	DISFVMRA	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Cardiofaciocutaneous syndrome	DISZJKSC	Strong	Altered Expression	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Leiomyoma	DISLDDFN	Strong	Genetic Variation	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[10]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[11]
Koolen-de Vries syndrome due to a point mutation	DISWVY1D	Supportive	Autosomal dominant	[12]
Androgenetic alopecia	DISSJR1P	Limited	Genetic Variation	[13]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[13]
Intellectual disability	DISMBNXP	Limited	Biomarker	[14]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[15]
Uterine fibroids	DISBZRMJ	Limited	Biomarker	[16]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of KAT8 regulatory NSL complex subunit 1 (KANSL1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of KAT8 regulatory NSL complex subunit 1 (KANSL1).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of KAT8 regulatory NSL complex subunit 1 (KANSL1).	[22]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of KAT8 regulatory NSL complex subunit 1 (KANSL1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of KAT8 regulatory NSL complex subunit 1 (KANSL1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of KAT8 regulatory NSL complex subunit 1 (KANSL1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of KAT8 regulatory NSL complex subunit 1 (KANSL1).	[23]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Risk of ovarian cancer and inherited variants in relapse-associated genes.PLoS One. 2010 Jan 27;5(1):e8884. doi: 10.1371/journal.pone.0008884.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] KANSL1 gene disruption associated with the full clinical spectrum of 17q21.31 microdeletion syndrome.BMC Med Genet. 2015 Aug 22;16:68. doi: 10.1186/s12881-015-0211-0.
• [5] The epileptology of Koolen-de Vries syndrome: Electro-clinico-radiologic findings in 31 patients.Epilepsia. 2017 Jun;58(6):1085-1094. doi: 10.1111/epi.13746. Epub 2017 Apr 25.
• [6] Genetic heterogeneity in leiomyomas of deep soft tissue.Oncotarget. 2017 Jul 25;8(30):48769-48781. doi: 10.18632/oncotarget.17953.
• [7] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [8] Characterization of fusion genes in common and rare epithelial ovarian cancer histologic subtypes.Oncotarget. 2017 Jul 18;8(29):46891-46899. doi: 10.18632/oncotarget.16781.
• [9] A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.Nat Genet. 2019 May;51(5):815-823. doi: 10.1038/s41588-019-0395-x. Epub 2019 May 1.
• [10] Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.
• [11] The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.Eur J Hum Genet. 2016 May;24(5):652-9. doi: 10.1038/ejhg.2015.178. Epub 2015 Aug 26.
• [12] Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012 Apr 29;44(6):639-41. doi: 10.1038/ng.2262.
• [13] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [14] KANSL1 variation is not a major contributing factor in self-limited focal epilepsy syndromes of childhood.PLoS One. 2018 Jan 19;13(1):e0191546. doi: 10.1371/journal.pone.0191546. eCollection 2018.
• [15] Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.Hum Mol Genet. 2014 Sep 1;23(17):4693-702. doi: 10.1093/hmg/ddu158. Epub 2014 May 19.
• [16] Leiomyoma with KAT6B-KANSL1 fusion: case report of a rapidly enlarging uterine mass in a postmenopausal woman.Diagn Pathol. 2019 Apr 25;14(1):32. doi: 10.1186/s13000-019-0809-1.
• [17] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.