Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUBW5PV)

• DOT Name: Transcription factor ATOH7 (ATOH7)
• Synonyms: Atonal bHLH transcription factor 7; Class A basic helix-loop-helix protein 13; bHLHa13; Protein atonal homolog 7
• Gene Name: ATOH7
• Related Disease:
  Angle-closure glaucoma
  Autism
  Blindness
  Coloboma
  Glaucoma/ocular hypertension
  Persistent hyperplastic primary vitreous, autosomal recessive
  Primary angle-closure glaucoma
  Retinopathy
  High blood pressure
  Anterior segment dysgenesis 7
  Persistent hyperplastic primary vitreous
  Isolated optic nerve hypoplasia
• UniProt ID: ATOH7_HUMAN
• Pfam ID: PF00010
• Sequence:
  MKSCKPSGPPAGARVAPPCAGGTECAGTCAGAGRLESAARRRLAANARERRRMQGLNTAF
  DRLRRVVPQWGQDKKLSKYETLQMALSYIMALTRILAEAERFGSERDWVGLHCEHFGRDH
  YLPFPGAKLPGESELYSQRLFGFQPEPFQMAT
• Function: Transcription factor that binds to DNA at the consensus sequence 5'-CAG[GC]TG-3'. Dimerization with TCF3 isoform E47 may be required in certain situations. Binds to gene promoters and enhancer elements, and thereby regulates a transcriptional program of retinal ganglion cell (RGC) determinant genes. Although the exact mechanism is not certain, retinal transcription regulation by ATOH7 has a role in RGC determination and survival, photoreceptor population development, targeting of RGC axons to the optic nerve and development of the retino-hypothalamic tract. Binds to its own promoter and enhancer sequences, suggesting autoregulation of ATOH7 transcription. Required for retinal circadian rhythm photoentrainment. Plays a role in brainstem auditory signaling and binaural processing.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angle-closure glaucoma	DISZ95KY	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Blindness	DISTIM10	Strong	Genetic Variation	[3]
Coloboma	DISP39N5	Strong	Genetic Variation	[4]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Biomarker	[5]
Persistent hyperplastic primary vitreous, autosomal recessive	DISUK45U	Strong	Autosomal recessive	[6]
Primary angle-closure glaucoma	DISX8UKZ	Strong	Biomarker	[1]
Retinopathy	DISB4B0F	Strong	Biomarker	[7]
High blood pressure	DISY2OHH	moderate	Biomarker	[8]
Anterior segment dysgenesis 7	DISP6CEE	Supportive	Autosomal recessive	[9]
Persistent hyperplastic primary vitreous	DISABPH6	Supportive	Autosomal dominant	[7]
Isolated optic nerve hypoplasia	DISFFR14	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transcription factor ATOH7 (ATOH7).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transcription factor ATOH7 (ATOH7).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Transcription factor ATOH7 (ATOH7).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription factor ATOH7 (ATOH7).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor ATOH7 (ATOH7).	[14]

References

• [1] Advances in glaucoma genetics.Prog Brain Res. 2015;220:107-26. doi: 10.1016/bs.pbr.2015.04.006. Epub 2015 Jul 2.
• [2] Morphometric analysis and neuroanatomical mapping of the zebrafish brain.Methods. 2018 Nov 1;150:49-62. doi: 10.1016/j.ymeth.2018.06.008. Epub 2018 Jun 21.
• [3] Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.Hum Mol Genet. 2010 Jul 1;19(13):2716-24. doi: 10.1093/hmg/ddq144. Epub 2010 Apr 15.
• [4] The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014 Aug;57(8):369-80. doi: 10.1016/j.ejmg.2014.05.002. Epub 2014 May 22.
• [5] Clarifying the role of ATOH7 in glaucoma endophenotypes.Br J Ophthalmol. 2014 Apr;98(4):562-6. doi: 10.1136/bjophthalmol-2013-304080. Epub 2014 Jan 23.
• [6] Math5 is required for retinal ganglion cell and optic nerve formation. Development. 2001 Jul;128(13):2497-508. doi: 10.1242/dev.128.13.2497.
• [7] ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. Hum Mol Genet. 2012 Aug 15;21(16):3681-94. doi: 10.1093/hmg/dds197. Epub 2012 May 29.
• [8] The polymorphisms of ATOH 7, ET-1 and ACE in non-arteritic anterior ischemic optic neuropathy.Exp Eye Res. 2018 Sep;174:147-151. doi: 10.1016/j.exer.2018.05.021. Epub 2018 May 21.
• [9] Next generation sequencing identifies mutations in Atonal homolog 7 (ATOH7) in families with global eye developmental defects. Hum Mol Genet. 2012 Feb 15;21(4):776-83. doi: 10.1093/hmg/ddr509. Epub 2011 Nov 7.
• [10] Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia.Hum Mol Genet. 2020 Jan 1;29(1):132-148. doi: 10.1093/hmg/ddz268.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] 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.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.