ID   ATOH8_HUMAN             Reviewed;         321 AA.
AC   Q96SQ7; Q504S2; Q659B0;
DT   18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT   03-MAR-2009, sequence version 2.
DT   27-MAR-2024, entry version 162.
DE   RecName: Full=Transcription factor ATOH8 {ECO:0000305};
DE   AltName: Full=Class A basic helix-loop-helix protein 21 {ECO:0000312|HGNC:HGNC:24126};
DE            Short=bHLHa21 {ECO:0000312|HGNC:HGNC:24126};
DE   AltName: Full=Helix-loop-helix protein hATH-6 {ECO:0000312|EMBL:AAO85773.1};
DE            Short=hATH6 {ECO:0000303|PubMed:24463812};
DE   AltName: Full=Protein atonal homolog 8 {ECO:0000312|HGNC:HGNC:24126};
GN   Name=ATOH8 {ECO:0000312|HGNC:HGNC:24126}; Synonyms=ATH6, BHLHA21;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT PRO-150, AND TISSUE
RP   SPECIFICITY.
RC   TISSUE=Umbilical vein;
RX   PubMed=12419857; DOI=10.1152/physiolgenomics.00102.2002;
RA   Wasserman S.M., Mehraban F., Komuves L.G., Yang R.B., Tomlinson J.E.,
RA   Zhang Y., Spriggs F., Topper J.N.;
RT   "Gene expression profile of human endothelial cells exposed to sustained
RT   fluid shear stress.";
RL   Physiol. Genomics 12:13-23(2002).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT PRO-150.
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT PRO-150.
RC   TISSUE=Muscle, and Retinal pigment epithelium;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 154-321 (ISOFORM 2).
RC   TISSUE=Amygdala;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
RN   [6]
RP   FUNCTION.
RX   PubMed=24236640; DOI=10.1111/bjh.12649;
RA   Patel N., Varghese J., Masaratana P., Latunde-Dada G.O., Jacob M.,
RA   Simpson R.J., McKie A.T.;
RT   "The transcription factor ATOH8 is regulated by erythropoietic activity and
RT   regulates HAMP transcription and cellular pSMAD1,5,8 levels.";
RL   Br. J. Haematol. 164:586-596(2014).
RN   [7]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=24463812; DOI=10.1242/jcs.136358;
RA   Fang F., Wasserman S.M., Torres-Vazquez J., Weinstein B., Cao F., Li Z.,
RA   Wilson K.D., Yue W., Wu J.C., Xie X., Pei X.;
RT   "The role of Hath6, a newly identified shear-stress-responsive
RT   transcription factor, in endothelial cell differentiation and function.";
RL   J. Cell Sci. 127:1428-1440(2014).
CC   -!- FUNCTION: Transcription factor that binds a palindromic (canonical)
CC       core consensus DNA sequence 5'-CANNTG- 3' known as an E-box element,
CC       possibly as a heterodimer with other bHLH proteins (PubMed:24236640).
CC       Regulates endothelial cell proliferation, migration and tube-like
CC       structures formation (PubMed:24463812). Modulates endothelial cell
CC       differentiation through NOS3 (PubMed:24463812). May be implicated in
CC       specification and differentiation of neuronal cell lineages in the
CC       brain (By similarity). May participate in kidney development and may be
CC       involved in podocyte differentiation (By similarity). During early
CC       embryonic development is involved in tissue-specific differentiation
CC       processes that are dependent on class II bHLH factors and namely
CC       modulates the differentiation program initiated by the pro-endocrine
CC       factor NEUROG3 (By similarity). During myogenesis, may play a role
CC       during the transition of myoblasts from the proliferative phase to the
CC       differentiation phase (By similarity). Positively regulates HAMP
CC       transcription in two ways, firstly by acting directly on the HAMP
CC       promoter via E-boxes binding and indirectly through increased
CC       phosphorylation of SMAD protein complex (PubMed:24236640). Repress
CC       NEUROG3-dependent gene activation in a gene-specific manner through at
CC       least two mechanisms; requires only either the sequestering of a
CC       general partner such as TCF3 through heterodimerization, either also
CC       requires binding of the bHLH domain to DNA via a basic motif (By
CC       similarity). {ECO:0000250|UniProtKB:Q99NA2,
CC       ECO:0000269|PubMed:24236640, ECO:0000269|PubMed:24463812}.
CC   -!- SUBUNIT: Efficient DNA binding requires dimerization with another bHLH
CC       protein. Interacts with NEUROG3 and NEUROD1. Interacts with ZFPM2;
CC       mediates indirect interaction with GATA4. Forms a heterodimer with
CC       TCF3; repress transcription of TCF3 and TCF3/NEUROG3 dimer-induced
CC       transactivation of E box-dependent promoters.
CC       {ECO:0000250|UniProtKB:Q99NA2}.
CC   -!- INTERACTION:
CC       Q96SQ7-1; P16298-4: PPP3CB; NbExp=5; IntAct=EBI-26429573, EBI-26442038;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:24463812}. Nucleus
CC       speckle {ECO:0000269|PubMed:24463812}. Cytoplasm
CC       {ECO:0000250|UniProtKB:Q99NA2}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q96SQ7-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q96SQ7-2; Sequence=VSP_032118;
CC   -!- TISSUE SPECIFICITY: Expressed in lung, liver, kidney, heart and
CC       pancreas. Expressed in endothel of umbilical vessels.
CC       {ECO:0000269|PubMed:12419857}.
CC   -!- DOMAIN: The bHLH domain mediates transcriptional repression by
CC       inhibiting TCF3 transcriptional activity through heterodimerization.
CC       {ECO:0000250|UniProtKB:Q99NA2}.
CC   -!- CAUTION: Contains a degenerate basic motif not likely to bind DNA.
CC       {ECO:0000255|PROSITE-ProRule:PRU00981}.
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DR   EMBL; AF529205; AAO85773.1; -; mRNA.
DR   EMBL; AK027614; BAB55233.1; -; mRNA.
DR   EMBL; AK074681; BAC11135.1; -; mRNA.
DR   EMBL; AC012454; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC021207; AAH21207.1; -; mRNA.
DR   EMBL; BC094832; AAH94832.1; -; mRNA.
DR   EMBL; AL831857; CAH56263.1; -; mRNA.
DR   CCDS; CCDS1985.1; -. [Q96SQ7-1]
DR   RefSeq; NP_116216.2; NM_032827.6. [Q96SQ7-1]
DR   AlphaFoldDB; Q96SQ7; -.
DR   SMR; Q96SQ7; -.
DR   BioGRID; 124350; 3.
DR   IntAct; Q96SQ7; 3.
DR   STRING; 9606.ENSP00000304676; -.
DR   iPTMnet; Q96SQ7; -.
DR   PhosphoSitePlus; Q96SQ7; -.
DR   BioMuta; ATOH8; -.
DR   DMDM; 224471820; -.
DR   jPOST; Q96SQ7; -.
DR   MassIVE; Q96SQ7; -.
DR   PaxDb; 9606-ENSP00000304676; -.
DR   PeptideAtlas; Q96SQ7; -.
DR   ProteomicsDB; 78136; -. [Q96SQ7-1]
DR   ProteomicsDB; 78137; -. [Q96SQ7-2]
DR   Antibodypedia; 17011; 158 antibodies from 26 providers.
DR   DNASU; 84913; -.
DR   Ensembl; ENST00000306279.4; ENSP00000304676.3; ENSG00000168874.13. [Q96SQ7-1]
DR   GeneID; 84913; -.
DR   KEGG; hsa:84913; -.
DR   MANE-Select; ENST00000306279.4; ENSP00000304676.3; NM_032827.7; NP_116216.2.
DR   UCSC; uc002sqn.4; human. [Q96SQ7-1]
DR   AGR; HGNC:24126; -.
DR   CTD; 84913; -.
DR   DisGeNET; 84913; -.
DR   GeneCards; ATOH8; -.
DR   HGNC; HGNC:24126; ATOH8.
DR   HPA; ENSG00000168874; Tissue enhanced (skeletal).
DR   MIM; 619820; gene.
DR   neXtProt; NX_Q96SQ7; -.
DR   OpenTargets; ENSG00000168874; -.
DR   PharmGKB; PA134904746; -.
DR   VEuPathDB; HostDB:ENSG00000168874; -.
DR   eggNOG; KOG3898; Eukaryota.
DR   GeneTree; ENSGT00940000161151; -.
DR   HOGENOM; CLU_057987_0_0_1; -.
DR   InParanoid; Q96SQ7; -.
DR   OMA; QKVLCER; -.
DR   OrthoDB; 2883823at2759; -.
DR   PhylomeDB; Q96SQ7; -.
DR   TreeFam; TF324848; -.
DR   PathwayCommons; Q96SQ7; -.
DR   SignaLink; Q96SQ7; -.
DR   BioGRID-ORCS; 84913; 14 hits in 1167 CRISPR screens.
DR   GenomeRNAi; 84913; -.
DR   Pharos; Q96SQ7; Tbio.
DR   PRO; PR:Q96SQ7; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q96SQ7; Protein.
DR   Bgee; ENSG00000168874; Expressed in right lobe of thyroid gland and 163 other cell types or tissues.
DR   GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR   GO; GO:0140297; F:DNA-binding transcription factor binding; IEA:Ensembl.
DR   GO; GO:0070888; F:E-box binding; IDA:UniProtKB.
DR   GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR   GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR   GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR   GO; GO:0001704; P:formation of primary germ layer; ISS:UniProtKB.
DR   GO; GO:0051450; P:myoblast proliferation; ISS:UniProtKB.
DR   GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IMP:UniProtKB.
DR   GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL.
DR   GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB.
DR   GO; GO:0045603; P:positive regulation of endothelial cell differentiation; IDA:UniProtKB.
DR   GO; GO:0010595; P:positive regulation of endothelial cell migration; IMP:UniProtKB.
DR   GO; GO:1902895; P:positive regulation of miRNA transcription; IGI:BHF-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0060395; P:SMAD protein signal transduction; IDA:UniProtKB.
DR   GO; GO:0035148; P:tube formation; IMP:UniProtKB.
DR   CDD; cd11421; bHLH_TS_ATOH8; 1.
DR   Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1.
DR   InterPro; IPR032660; ATOH8_bHLH.
DR   InterPro; IPR011598; bHLH_dom.
DR   InterPro; IPR036638; HLH_DNA-bd_sf.
DR   PANTHER; PTHR19290; BASIC HELIX-LOOP-HELIX PROTEIN NEUROGENIN-RELATED; 1.
DR   PANTHER; PTHR19290:SF102; TRANSCRIPTION FACTOR ATOH8; 1.
DR   Pfam; PF00010; HLH; 1.
DR   SMART; SM00353; HLH; 1.
DR   SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1.
DR   PROSITE; PS50888; BHLH; 1.
DR   Genevisible; Q96SQ7; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cytoplasm; Developmental protein; Differentiation;
KW   DNA-binding; Neurogenesis; Nucleus; Reference proteome; Transcription;
KW   Transcription regulation.
FT   CHAIN           1..321
FT                   /note="Transcription factor ATOH8"
FT                   /id="PRO_0000323751"
FT   DOMAIN          230..282
FT                   /note="bHLH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT   REGION          59..193
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          203..222
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          230..243
FT                   /note="Basic motif; degenerate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT   REGION          244..282
FT                   /note="Helix-loop-helix motif"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT   COMPBIAS        70..84
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        119..137
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        158..182
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VAR_SEQ         321
FT                   /note="E -> SLIITQDTTARAAGLEAAGKTVQKVLCERGNSLMNNRTGRRKSWRLE
FT                   FLFLRRRCFLLTFYLWFLFFSRFLLMLFLPLLTSVVTFLPPLRARRPPH (in
FT                   isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:17974005"
FT                   /id="VSP_032118"
FT   VARIANT         150
FT                   /note="L -> P (in dbSNP:rs17851881)"
FT                   /evidence="ECO:0000269|PubMed:12419857,
FT                   ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334"
FT                   /id="VAR_039582"
SQ   SEQUENCE   321 AA;  34644 MW;  6AEC8043AD8D2075 CRC64;
     MKHIPVLEDG PWKTVCVKEL NGLKKLKRKG KEPARRANGY KTFRLDLEAP EPRAVATNGL
     RDRTHRLQPV PVPVPVPVPV APAVPPRGGT DTAGERGGSR APEVSDARKR CFALGAVGPG
     LPTPPPPPPP APQSQAPGGP EAQPFREPGL RPRILLCAPP ARPAPSAPPA PPAPPESTVR
     PAPPTRPGES SYSSISHVIY NNHQDSSASP RKRPGEATAA SSEIKALQQT RRLLANARER
     TRVHTISAAF EALRKQVPCY SYGQKLSKLA ILRIACNYIL SLARLADLDY SADHSNLSFS
     ECVQRCTRTL QAEGRAKKRK E
//