Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO7EJIS)

• DOT Name: Actin-like protein 6B (ACTL6B)
• Synonyms: 53 kDa BRG1-associated factor B; Actin-related protein Baf53b; ArpNalpha; BRG1-associated factor 53B; BAF53B
• Gene Name: ACTL6B
• Related Disease:
  Developmental and epileptic encephalopathy, 76
  Brain disease
  Intellectual developmental disorder with severe speech and ambulation defects
  Intellectual disability
  Neurodevelopmental disorder
  Syndromic intellectual disability
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: ACL6B_HUMAN
• Pfam ID: PF00022
• Sequence:
  MSGGVYGGDEVGALVFDIGSFSVRAGYAGEDCPKADFPTTVGLLAAEEGGGLELEGDKEK
  KGKIFHIDTNALHVPRDGAEVMSPLKNGMIEDWECFRAILDHTYSKHVKSEPNLHPVLMS
  EAPWNTRAKREKLTELMFEQYNIPAFFLCKTAVLTAFANGRSTGLVLDSGATHTTAIPVH
  DGYVLQQGIVKSPLAGDFISMQCRELFQEMAIDIIPPYMIAAKEPVREGAPPNWKKKEKL
  PQVSKSWHNYMCNEVIQDFQASVLQVSDSPYDEQVAAQMPTVHYEMPNGYNTDYGAERLR
  IPEGLFDPSNVKGLSGNTMLGVGHVVTTSIGMCDIDIRPGLYGSVIVTGGNTLLQGFTDR
  LNRELSQKTPPSMRLKLIASNSTMERKFSPWIGGSILASLGTFQQMWISKQEYEEGGKQC
  VERKCP
• Function: Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Belongs to the neuron-specific chromatin remodeling complex (nBAF complex), as such plays a role in remodeling mononucleosomes in an ATP-dependent fashion, and is required for postmitotic neural development and dendritic outgrowth. During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. ACTL6B/BAF53B is not essential for assembly of the nBAF complex but is required for targeting the complex and CREST to the promoter of genes essential for dendritic growth. Essential for neuronal maturation and dendrite development.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Thermogenesis (hsa04714)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway:
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  RMTs methylate histone arginines (R-HSA-3214858)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 76	DISH4XWH	Definitive	Autosomal recessive	[1]
Brain disease	DIS6ZC3X	Strong	Biomarker	[2]
Intellectual developmental disorder with severe speech and ambulation defects	DISXCWBJ	Strong	Autosomal dominant	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[1]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[2]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Actin-like protein 6B (ACTL6B).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Actin-like protein 6B (ACTL6B).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Actin-like protein 6B (ACTL6B).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Actin-like protein 6B (ACTL6B).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Actin-like protein 6B (ACTL6B).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Actin-like protein 6B (ACTL6B).	[10]

References

• [1] Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy. Hum Genet. 2019 Feb;138(2):187-198. doi: 10.1007/s00439-019-01972-3. Epub 2019 Jan 17.
• [2] Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons. Am J Hum Genet. 2019 May 2;104(5):815-834. doi: 10.1016/j.ajhg.2019.03.022. Epub 2019 Apr 25.
• [3] The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nat Neurosci. 2013 May;16(5):552-61. doi: 10.1038/nn.3359. Epub 2013 Mar 24.
• [4] Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019 Mar;21(3):736-742. doi: 10.1038/s41436-018-0138-x. Epub 2018 Sep 21.
• [5] 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.
• [6] Differential responses to retinoic acid and endocrine disruptor compounds of subpopulations within human embryonic stem cell lines. Differentiation. 2012 Nov;84(4):330-43. doi: 10.1016/j.diff.2012.07.006. Epub 2012 Aug 18.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] 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.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.