ID HLH2_CAEEL Reviewed; 399 AA. AC G5EEG9; Q17326; Q17358; DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot. DT 14-DEC-2011, sequence version 1. DT 25-MAY-2022, entry version 77. DE RecName: Full=Helix-loop-helix protein hlh-2 {ECO:0000312|WormBase:M05B5.5a}; GN Name=hlh-2 {ECO:0000312|WormBase:M05B5.5a}; GN ORFNames=M05B5.5 {ECO:0000312|WormBase:M05B5.5a}; OS Caenorhabditis elegans. OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida; OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae; OC Caenorhabditis. OX NCBI_TaxID=6239 {ECO:0000312|Proteomes:UP000001940}; RN [1] {ECO:0000312|EMBL:AAA21347.1, ECO:0000312|EMBL:AAC13874.1} RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RC STRAIN=Bristol N2 {ECO:0000312|EMBL:AAA21347.1, RC ECO:0000312|EMBL:AAC13874.1}; RA Krause M.W., Fire A.; RT "cDNA sequence of the C. elegans homolog of the vertebrate basic-helix- RT loop-helix transcription factor, E12/47."; RL Submitted (AUG-1994) to the EMBL/GenBank/DDBJ databases. RN [2] {ECO:0000312|Proteomes:UP000001940} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Bristol N2 {ECO:0000312|Proteomes:UP000001940}; RX PubMed=9851916; DOI=10.1126/science.282.5396.2012; RG The C. elegans sequencing consortium; RT "Genome sequence of the nematode C. elegans: a platform for investigating RT biology."; RL Science 282:2012-2018(1998). RN [3] {ECO:0000305} RP FUNCTION, INTERACTION WITH LIN-32, SUBCELLULAR LOCATION, DEVELOPMENTAL RP STAGE, AND MUTAGENESIS OF ARG-316 AND VAL-352. RX PubMed=11076762; DOI=10.1242/dev.127.24.5415; RA Portman D.S., Emmons S.W.; RT "The basic helix-loop-helix transcription factors LIN-32 and HLH-2 function RT together in multiple steps of a C. elegans neuronal sublineage."; RL Development 127:5415-5426(2000). RN [4] {ECO:0000305} RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE. RX PubMed=14701877; DOI=10.1101/gad.1160803; RA Karp X., Greenwald I.; RT "Post-transcriptional regulation of the E/Daughterless ortholog HLH-2, RT negative feedback, and birth order bias during the AC/VU decision in C. RT elegans."; RL Genes Dev. 17:3100-3111(2003). RN [5] {ECO:0000305} RP FUNCTION, INTERACTION WITH HLH-12, AND DISRUPTION PHENOTYPE. RX PubMed=17588558; DOI=10.1016/j.ydbio.2007.05.024; RA Tamai K.K., Nishiwaki K.; RT "bHLH transcription factors regulate organ morphogenesis via activation of RT an ADAMTS protease in C. elegans."; RL Dev. Biol. 308:562-571(2007). RN [6] {ECO:0000305} RP FUNCTION, INTERACTION WITH HLH-10, AND DEVELOPMENTAL STAGE. RX PubMed=19632181; DOI=10.1016/j.cell.2009.04.058; RA Grove C.A., De Masi F., Barrasa M.I., Newburger D.E., Alkema M.J., RA Bulyk M.L., Walhout A.J.M.; RT "A multiparameter network reveals extensive divergence between C. elegans RT bHLH transcription factors."; RL Cell 138:314-327(2009). RN [7] {ECO:0000305} RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE. RX PubMed=19376107; DOI=10.1016/j.ydbio.2009.04.015; RA Chesney M.A., Lam N., Morgan D.E., Phillips B.T., Kimble J.; RT "C. elegans HLH-2/E/Daughterless controls key regulatory cells during RT gonadogenesis."; RL Dev. Biol. 331:14-25(2009). RN [8] {ECO:0000305} RP FUNCTION, INTERACTION WITH NGN-1, DEVELOPMENTAL STAGE, AND DISRUPTION RP PHENOTYPE. RX PubMed=21041366; DOI=10.1242/dev.058834; RA Nakano S., Ellis R.E., Horvitz H.R.; RT "Otx-dependent expression of proneural bHLH genes establishes a neuronal RT bilateral asymmetry in C. elegans."; RL Development 137:4017-4027(2010). RN [9] {ECO:0000305} RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE. RX PubMed=21784067; DOI=10.1016/j.ydbio.2011.07.012; RA Schindler A.J., Sherwood D.R.; RT "The transcription factor HLH-2/E/Daughterless regulates anchor cell RT invasion across basement membrane in C. elegans."; RL Dev. Biol. 357:380-391(2011). RN [10] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=25982859; DOI=10.1016/j.gene.2015.05.030; RA Meighan C.M., Kann A.P., Egress E.R.; RT "Transcription factor hlh-2/E/Daughterless drives expression of alpha RT integrin ina-1 during DTC migration in C. elegans."; RL Gene 568:220-226(2015). RN [11] {ECO:0000305} RP FUNCTION, AND DEVELOPMENTAL STAGE. RX PubMed=31402303; DOI=10.1016/j.cub.2019.07.062; RA Attner M.A., Keil W., Benavidez J.M., Greenwald I.; RT "HLH-2/E2A Expression Links Stochastic and Deterministic Elements of a Cell RT Fate Decision during C. elegans Gonadogenesis."; RL Curr. Biol. 29:3094-3100(2019). RN [12] {ECO:0000305} RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=32203922; DOI=10.1016/j.redox.2020.101448; RA Rozanov L., Ravichandran M., Grigolon G., Zanellati M.C., Mansfeld J., RA Zarse K., Barzilai N., Atzmon G., Fischer F., Ristow M.; RT "Redox-mediated regulation of aging and healthspan by an evolutionarily RT conserved transcription factor HLH-2/Tcf3/E2A."; RL Redox Biol. 32:101448-101448(2020). CC -!- FUNCTION: Transcription factor which binds the E box motif 5'- CC CA[TC][AG]TG-3' (PubMed:19632181, PubMed:11076762, PubMed:14701877). CC Plays a key role in the anchor cell/ventral uterine precursor cell CC (AC/VU) decision; required for VU fate (PubMed:14701877, CC PubMed:31402303). Regulates expression of lin-12/Notch receptor and CC putative ligand lag-2 in the presumptive AC and presumptive VU cells CC (PubMed:31402303). Modulates expression of lag-2 in the gonadal distal CC tip cells (DTCs) (PubMed:14701877, PubMed:19376107). Involved in CC formation of the polarised cell membrane of the AC and thus facilitates CC invasion across the gonadal basement membrane, acting via CC transcriptional modulation of multiple genes (PubMed:21784067). CC Involved in specification of the hermaphrodite DTC and the male linker CC cell, perhaps acting in concert with the homeobox protein, ceh-22 CC (PubMed:19376107). Plays a role in regulation of migration of DTCs and CC the modulation of expression of alpha integrin ina-1 and ADAMTS CC protease gon-1 (PubMed:25982859, PubMed:17588558). Required for DTC CC maintenance, and for function of the DTC as a niche for germline stem CC cells (PubMed:19376107). Plays a role in cell-autonomously establishing CC a neuronal left-right asymmetry (PubMed:21041366). Required for CC specification of cell fate, acting in concert with lin-32, in the CC development of the male-specific genital sensilla (simple sense organs) CC known as rays (PubMed:11076762). Negatively modulates lifespan, perhaps CC acting by regulating expression of arginine kinases, which in turn CC results in altered metabolism and homeostasis of reactive oxygen CC species (ROS) (PubMed:32203922). {ECO:0000269|PubMed:11076762, CC ECO:0000269|PubMed:14701877, ECO:0000269|PubMed:17588558, CC ECO:0000269|PubMed:19376107, ECO:0000269|PubMed:19632181, CC ECO:0000269|PubMed:21041366, ECO:0000269|PubMed:21784067, CC ECO:0000269|PubMed:25982859, ECO:0000269|PubMed:31402303, CC ECO:0000269|PubMed:32203922}. CC -!- SUBUNIT: Interacts with helix-loop-helix protein ngn-1; the interaction CC is direct (PubMed:21041366). Efficient DNA binding probably requires CC dimerization with another helix-loop-helix protein (PubMed:19632181, CC PubMed:11076762). Forms a heterodimer with helix-loop-helix protein CC hlh-12 (PubMed:17588558). Forms a heterodimer with lin-32 CC (PubMed:11076762). May form a heterodimer with hlh-10 CC (PubMed:19632181). {ECO:0000269|PubMed:11076762, CC ECO:0000269|PubMed:17588558, ECO:0000269|PubMed:19632181, CC ECO:0000269|PubMed:21041366}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11076762}. CC -!- DEVELOPMENTAL STAGE: During male tail development, expressed in each of CC the nine Rn cells and in the anterior daughter cell, the ray neuroblast CC (at protein level) (PubMed:11076762). First expressed at the comma CC stage of embryogenesis (PubMed:19632181). Expressed asymmetrically, in CC the mother cell of the MI pharyngeal motorneuron but not in the mother CC cell of the e3D epithelial cell (PubMed:21041366). Expressed during CC hermaphrodite gonadogenesis, in the two somatic gonadal progenitor CC (SGP) cells, Z1.ppp and Z4.aaa, precursors to the anchor cell (AC) and CC the ventral uterine precursor cell (VU), but not detected in their CC sister cells, Z1.ppa and Z4.aap (PubMed:14701877, PubMed:19376107, CC PubMed:21784067). Expressed in both pre-AC and pre-VU cells, and after CC the AC/VU decision, expression is reduced in the VU and its CC descendants; however, expression persists in the AC through the time of CC basement membrane invasion (PubMed:21784067, PubMed:31402303). CC Expressed in the gonadal distal tip cells (DTCs) throughout development CC and in adults (PubMed:19376107). {ECO:0000269|PubMed:11076762, CC ECO:0000269|PubMed:14701877, ECO:0000269|PubMed:19376107, CC ECO:0000269|PubMed:19632181, ECO:0000269|PubMed:21041366, CC ECO:0000269|PubMed:21784067, ECO:0000269|PubMed:31402303}. CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown in the early larval L1 CC stage causes both somatic gonadal progenitor (SGP) cells, Z1.ppp and CC Z4.aaa, to assume the ventral uterine precursor cell (VU) identity; CC whereas, if RNAi is applied during the late larval L1 stage, or at the CC larval L2 stage, both assume the anchor cell (AC) identity CC (PubMed:21784067, PubMed:14701877). RNAi-mediated knockdown applied at CC the time of the larval stage L1/L2 molt causes defects in invasion of CC the basement membrane by the AC (PubMed:21784067). RNAi-mediated CC knockdown causes the MI pharyngeal motorneuron to transform into an CC e3D-like epithelial cell (PubMed:21041366). RNAi-mediated knockdown CC reduces expression of alpha integrin ina-1 and of ADAMTS protease gon- CC 1, and causes defects in migration of the gonadal distal tip cells CC (DTCs) (PubMed:25982859, PubMed:17588558). RNAi-mediated knockdown CC causes reduction in the number of hermaphrodites with DTCs, diminishes CC formation of elongated gonadal arms and reduces expression of lag-2 CC (PubMed:19376107). RNAi-mediated knockdown during larval stage L3 CC causes a subsequent three-fold reduction in germ cell number in the CC adult hermaphrodite gonad (PubMed:19376107). RNAi-mediated knockdown CC increases lifespan, reduces fertility, improves the response to CC proteotoxic stress, alters the response to reactive oxygen species CC (ROS) and reduces expression of arginine kinases such as argk-1 CC (PubMed:32203922). {ECO:0000269|PubMed:14701877, CC ECO:0000269|PubMed:17588558, ECO:0000269|PubMed:19376107, CC ECO:0000269|PubMed:21041366, ECO:0000269|PubMed:21784067, CC ECO:0000269|PubMed:25982859, ECO:0000269|PubMed:32203922}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U13614; AAA21347.1; -; mRNA. DR EMBL; U30248; AAC13874.1; -; Genomic_DNA. DR EMBL; BX284601; CAA95837.1; -; Genomic_DNA. DR PIR; T18853; T18853. DR RefSeq; NP_001021581.1; NM_001026410.3. DR AlphaFoldDB; G5EEG9; -. DR SMR; G5EEG9; -. DR IntAct; G5EEG9; 16. DR STRING; 6239.M05B5.5a; -. DR EPD; G5EEG9; -. DR PaxDb; G5EEG9; -. DR PeptideAtlas; G5EEG9; -. DR EnsemblMetazoa; M05B5.5a.1; M05B5.5a.1; WBGene00001949. DR GeneID; 172458; -. DR KEGG; cel:CELE_M05B5.5; -. DR CTD; 172458; -. DR WormBase; M05B5.5a; CE06191; WBGene00001949; hlh-2. DR eggNOG; KOG3910; Eukaryota. DR GeneTree; ENSGT00940000168822; -. DR HOGENOM; CLU_700646_0_0_1; -. DR InParanoid; G5EEG9; -. DR OMA; DAMSSMY; -. DR OrthoDB; 1442255at2759; -. DR PhylomeDB; G5EEG9; -. DR Reactome; R-CEL-525793; Myogenesis. DR Proteomes; UP000001940; Chromosome I. DR Bgee; WBGene00001949; Expressed in multi-cellular organism and 5 other tissues. DR GO; GO:0005737; C:cytoplasm; IDA:WormBase. DR GO; GO:0005634; C:nucleus; IDA:WormBase. DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IDA:WormBase. DR GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central. DR GO; GO:0043425; F:bHLH transcription factor binding; IPI:WormBase. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:WormBase. DR GO; GO:0046982; F:protein heterodimerization activity; IPI:WormBase. DR GO; GO:0042803; F:protein homodimerization activity; IPI:WormBase. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IMP:UniProtKB. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:WormBase. DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:WormBase. DR GO; GO:0046034; P:ATP metabolic process; IMP:UniProtKB. DR GO; GO:0034769; P:basement membrane disassembly; IMP:UniProtKB. DR GO; GO:0010171; P:body morphogenesis; IMP:WormBase. DR GO; GO:0001708; P:cell fate specification; IMP:UniProtKB. DR GO; GO:0008340; P:determination of adult lifespan; IMP:UniProtKB. DR GO; GO:0009792; P:embryo development ending in birth or egg hatching; IMP:WormBase. DR GO; GO:0030718; P:germ-line stem cell population maintenance; IMP:UniProtKB. DR GO; GO:0008406; P:gonad development; IMP:WormBase. DR GO; GO:0035262; P:gonad morphogenesis; IMP:UniProtKB. DR GO; GO:0042743; P:hydrogen peroxide metabolic process; IMP:UniProtKB. DR GO; GO:0002119; P:nematode larval development; IMP:WormBase. DR GO; GO:0045138; P:nematode male tail tip morphogenesis; IMP:WormBase. DR GO; GO:0014018; P:neuroblast fate specification; IMP:WormBase. DR GO; GO:0048666; P:neuron development; IGI:WormBase. DR GO; GO:0048665; P:neuron fate specification; IMP:UniProtKB. DR GO; GO:1903356; P:positive regulation of distal tip cell migration; IMP:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; IMP:WormBase. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:UniProtKB. DR GO; GO:2000114; P:regulation of establishment of cell polarity; IMP:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:WormBase. DR GO; GO:0000003; P:reproduction; IMP:WormBase. DR GO; GO:1990636; P:reproductive senescence; IMP:UniProtKB. DR GO; GO:0032094; P:response to food; IMP:UniProtKB. DR GO; GO:0040025; P:vulval development; IMP:UniProtKB. DR Gene3D; 4.10.280.10; -; 1. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR Pfam; PF00010; HLH; 1. DR SMART; SM00353; HLH; 1. DR SUPFAM; SSF47459; SSF47459; 1. DR PROSITE; PS50888; BHLH; 1. PE 1: Evidence at protein level; KW Developmental protein; DNA-binding; Neurogenesis; Nucleus; KW Reference proteome; Transcription; Transcription regulation. FT CHAIN 1..399 FT /note="Helix-loop-helix protein hlh-2" FT /id="PRO_0000453281" FT DOMAIN 302..356 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT REGION 66..119 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 208..315 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 302..315 FT /note="Basic motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT REGION 316..356 FT /note="Helix-loop-helix motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT REGION 371..399 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 248..291 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 292..315 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 372..386 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MUTAGEN 316 FT /note="R->H: In bx108; enhances the loss of male-specific FT genital sensilla (simple sense organs) known as rays, on a FT lin-32 mutant background. Slightly reduces binding to DNA FT as a heterodimer with lin-32." FT /evidence="ECO:0000269|PubMed:11076762" FT MUTAGEN 352 FT /note="V->M: In bx115; enhances the loss of male-specific FT genital sensilla (simple sense organs) known as rays, on a FT lin-32 mutant background. Causes defects in all three ray FT cell types. Slightly reduces binding to DNA as a FT heterodimer with lin-32." FT /evidence="ECO:0000269|PubMed:11076762" FT CONFLICT 210 FT /note="Q -> P (in Ref. 1; AAA21347/AAC13874)" FT /evidence="ECO:0000305" FT CONFLICT 224 FT /note="N -> H (in Ref. 1; AAA21347/AAC13874)" FT /evidence="ECO:0000305" FT CONFLICT 347 FT /note="H -> Y (in Ref. 1; AAA21347/AAC13874)" FT /evidence="ECO:0000305" SQ SEQUENCE 399 AA; 43193 MW; 8E139D03E597863B CRC64; MADPNSQLTS ATTVATAAIA QPQVMLPNAY DYPYNIDPTT IQMPDYWSGY HLNPYPPMQT TDIDYSSAFL PTHPPTETPA SVAAPTSATS DIKPIHATSS TSTTAPSTAP APTSTTDVLE LKPTTAPATN SAETSAIVAP QPLTNLTAPI DAMSSMYTWP QTYPGYLPPS EDNKASEAVN PYISIPPTYT FGADPSVADF SSYQQQLAGQ PNGLGGDTNL VDYNHQFPPA GMSPHFDPNG YPGMTGMPPG SSASSVRNDK SASRATSRRR VQGPPSSGIP TRHSSSSRLS DNESMSDDKD TDRRSQNNAR ERVRVRDINS AFKELGRMCT QHNQNTERNQ TKLGILHNAV SVITQLEEQV RQRNMNPKVM AGMKRKPDDD KMKMLDDNAP SAQFGHPRF //