# HISTORY 24 Mar 2016: Updated by: TOUCHUP-v1.15 14 Mar 2016: Updated by: TOUCHUP-v1.12 # molecular_function 20110804: Bilateria_PTN000042967 has function beta-catenin binding (GO:0008013) 20110804: Bilateria_PTN000042967 has function transcription regulatory region DNA binding (GO:0044212) 20110804: Bilateria_PTN000042967 has function sequence-specific DNA binding (GO:0043565) 20110804: Euteleostomi_PTN000042971 has function transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding (GO:0003705) 20110804: Euteleostomi_PTN000042971 has function estrogen receptor binding (GO:0030331) 20110804: Euteleostomi_PTN000042971 has function armadillo repeat domain binding (GO:0070016) 20110804: Euteleostomi_PTN000042971 has function gamma-catenin binding (GO:0045295) 20110804: Euteleostomi_PTN000042971 has function enhancer binding (GO:0035326) # cellular_component 20110804: Bilateria_PTN000042967 is found in transcription factor complex (GO:0005667) 20110804: Euteleostomi_PTN000042971 is found in cytoplasm (GO:0005737) # biological_process 20110805: Bilateria_PTN000042967 participates in canonical Wnt signaling pathway (GO:0060070) 20110805: Bilateria_PTN000042967 participates in regulation of transcription from RNA polymerase II promoter (GO:0006357) 20110805: Euteleostomi_PTN000042971 participates in hypothalamus development (GO:0021854) 20110810: Euteleostomi_PTN000042971 participates in positive regulation of cell proliferation in bone marrow (GO:0071864) 20110810: Euteleostomi_PTN000042971 participates in negative regulation of apoptotic process in bone marrow (GO:0071866) 20110805: Euteleostomi_PTN000042971 participates in negative regulation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0043154) 20110810: Euteleostomi_PTN000042971 participates in apoptotic process involved in morphogenesis (GO:0060561) 20110805: Euteleostomi_PTN000042971 participates in negative regulation of interleukin-5 production (GO:0032714) 20110805: Euteleostomi_PTN000042971 participates in regulation of striated muscle tissue development (GO:0016202) 20110805: Euteleostomi_PTN000042971 participates in muscle fiber development (GO:0048747) 20110805: Euteleostomi_PTN000042971 participates in formation of radial glial scaffolds (GO:0021943) 20110805: Euteleostomi_PTN000042971 participates in negative regulation of interleukin-13 production (GO:0032696) 20110805: Euteleostomi_PTN000042971 participates in mammary gland development (GO:0030879) 20110810: Euteleostomi_PTN000042971 participates in neutrophil differentiation (GO:0030223) 20110805: Euteleostomi_PTN000042971 participates in dentate gyrus development (GO:0021542) 20110805: Euteleostomi_PTN000042971 participates in negative regulation of interleukin-4 production (GO:0032713) 20110805: Euteleostomi_PTN000042971 participates in eye pigmentation (GO:0048069) 20110805: Euteleostomi_PTN000042971 participates in sprouting angiogenesis (GO:0002040) 20110805: Euteleostomi_PTN000042971 participates in trachea gland development (GO:0061153) 20110810: Euteleostomi_PTN000042971 participates in osteoblast differentiation (GO:0001649) 20110805: Euteleostomi_PTN000042971 participates in embryonic limb morphogenesis (GO:0030326) 20110810: Euteleostomi_PTN000042971 participates in alpha-beta T cell differentiation (GO:0046632) 20110810: Euteleostomi_PTN000042971 participates in paraxial mesoderm formation (GO:0048341) 20110805: Euteleostomi_PTN000042971 participates in forebrain neuroblast division (GO:0021873) 20110810: Euteleostomi_PTN000042971 participates in epithelial to mesenchymal transition (GO:0001837) 20110810: Euteleostomi_PTN000042971 participates in regulation of cell-cell adhesion (GO:0022407) 20110805: Euteleostomi_PTN000042971 participates in forebrain radial glial cell differentiation (GO:0021861) 20110810: Euteleostomi_PTN000042971 participates in neural crest cell migration (GO:0001755) 20110810: Euteleostomi_PTN000042971 participates in B cell proliferation (GO:0042100) 20110810: Euteleostomi_PTN000042971 participates in odontoblast differentiation (GO:0071895) 20110805: Euteleostomi_PTN000042971 participates in BMP signaling pathway (GO:0030509) 20110805: Euteleostomi_PTN000042971 participates in patterning of blood vessels (GO:0001569) 20110805: Euteleostomi_PTN000042971 participates in face morphogenesis (GO:0060325) 20110805: Euteleostomi_PTN000042971 participates in forebrain neuron differentiation (GO:0021879) 20110810: Euteleostomi_PTN000042971 participates in somitogenesis (GO:0001756) 20110810: Amniota_PTN000042973 participates in chorio-allantoic fusion (GO:0060710) 20110805: Teleostei_PTN001310325 does NOT participate in mammary gland development (GO:0030879) 20110805: Sauria_PTN001310323 does NOT participate in mammary gland development (GO:0030879) 20110810: Sauria_PTN001310323 does NOT participate in chorio-allantoic fusion (GO:0060710) # WARNINGS - THE FOLLOWING HAVE BEEN REMOVED FOR THE REASONS NOTED # NOTES Curation of PTHR10373:SF11 (the LEF1 subfamily) for the Wnt project Phylogeny and scope Subfamily 11 of PTHR10373 consists of the LEF1 (lymphoid enhancer binding factor) clade and is descended from AN4. This is one of three vertebrate clades in the family, the others being TCF7 and TCF7-like proteins. The worm and fly outgroups are represented by pop-1 and pan, respectively. There are no more distant proteins represented. Curation here is focused on the LEF1 clade and only ventures outside it for the most conserved functions. There are no annotations propagated within the TCF7 or TCF7-like clades. MF DNA binding & transcription factor activities -There are widespread annotations to children of GO:0003677 "DNA binding," with annotations in all clades. Propagate to AN0. This may get more specific as we go on. -It did. Propagate GO:0043565 "sequence-specific DNA binding" and GO:0044212 transcription regulatory region DNA binding to AN0. -Propagate GO:0003700 "sequence-specific DNA binding transcription factor activity" to all vertebrates based on widespread annotations. -Human LEF1 is annotated to GO:0035326 "enhancer binding" based on binding to the HIV enhancer as seen in PMID 7657162. Mouse Lef1 is annotated to GO:0003705 "sequence-specific enhancer binding RNA polymerase II transcription factor activity" based on PMID 15729346. Although there is no direct link between these terms (see question to ontology curators, below), the HIV enhancer is a specific sequence and uses RNA pol II. Therefore, propagate both terms to the LEF1 clade with the implied understanding that 35326 is redundant in the context of 3705. -Propagate GO:0003682 "chromatin binding" to the vertebrates based on many annotations to the three mouse proteins. Proteins -GO:0008134 "transcription factor binding" from mouse Lef is too nonspecific to propagate. Maybe if it specified a domain that Lef1 binds to, but not simply "TF binding." Similarly, do not propagate GO:0070742 "C2H2 zinc finger domain binding" from human because there are so many different zinc fingers and the function might not be conserved. -Propagate GO:0070016 "armadillo repeat domain binding" form human to the LEF1 clade. Armadillo domains are characteristic of beta-catenin. Based on widespread annotations in every clade, propagate GO:0008013 "beta-catenin binding" to AN0, but do not change the scope of 70016 because the interaction could be through any part of the protein. Propagate GO:0045295 "gamma-catenin binding" from human to the LEF1 clade. -Propagate GO:0030331 "estrogen receptor binding" from human to the LEF1 clade. Do not propagate GO:0030284 "estrogen receptor activity" from human LEF1 pending resolution of curator question, below. -Do not propagate the GO:0043027 "caspase inhibitor activity" IMP because it is probably a BP, not a MF (see question and BP annotation below). CC -There are annotations to GO:0005667 "transcription factor complex" on human and mouse LEF1, mouse Tcf7l2, and fly pan, and there are annotations to the MF GO:0003700 "sequence-specific DNA binding transcription factor activity" on all the vertebrates (above), so propagate 5667 to AN0. In this context, an annotation to GO:0032993 "protein-DNA complex" doesn't add anything, so don't propagate it. -Propagate GO:0005737 "cytoplasm" to LEF1 clade from human, mouse, and fish. BP This time, let's start with transcription-related terms, since this is a transcription factor. Transcription -There are annotations to GO:0006355 "regulation of transcription, DNA-dependent" throughout the family in every clade. Propagate to AN0. Don't propagate "positive" or "negative" children, as they are too specific. Do look for more specific mechanistic terms. -More specific: propagate GO:0006357 "regulation of transcription from RNA polymerase II promoter" to AN0 based on widespread annotation to all clades. Again, don't propagate "positive" or "negative" children, as they are too specific. -Do not propagate GO:0043923 "positive regulation by host of viral transcription," which come from an HIV paper (PMID 7657162) since HIV-1 is human-specific. Signaling -Annotations to GO:0016055 "Wnt receptor signaling pathway" are found throughout the family in every clade. Propagate to AN0. Annotations to the child term GO:0060070 "canonical Wnt receptor signaling pathway," which specifies that the pathway must proceed through beta-catenin and result in a transcriptional change, are found in the LEF1 and TCF7L2 clades, but not in the TCF7L1 clade or the fly/worm outgroup. However, since this is a family of transcription factors, the pathway includes a transcriptional change. The question is: does it proceed through a beta-catenin intermediate? Checking the TCF7L1 and outgroup clades reveals that the pathway in PMID 11057671 (Danio tcf7l1a) proceeds through beta-catenin. Also, UniProt notes that worm pop-1 (Q10666) interacts with bar-1, which is a homolog of beta-catenin, and that fly pan (Q8IMA8) binds to the beta-catenin homolog arm. Therefore, the pathway proceeds through beta-catenin in every clade of this family, so propagate 60070 to AN0. -Do not propagate any "regulation of" Wnt pathway terms for this family of transcription factors. -Propagate GO:0030509 "BMP signaling pathway" from mouse to LEF1 clade. -Propagate GO:0030520 "estrogen receptor signaling pathway" from human to LEF1 clade. Other subcellular processes -Propagate GO:0043154 "negative regulation of caspase activity" from PMID 20360943 instead of the MF "caspase inhibitor activity" from the same paper. See MF above and question below. -Do not propagate the histone H3 or H4 acetylation annotations from human LEF1 as they are IMP's and incidental to regulation of gene expression (PMID 20363964). -Propagate the following from human (PMID 18445004) to LEF1 clade: GO:0032713 negative regulation of interleukin-4 production GO:0032714 negative regulation of interleukin-5 production GO:0032696 negative regulation of interleukin-13 production -Do not propagate the terms GO:0071899 "negative regulation of estrogen receptor binding" or GO:0043392 "negative regulation of DNA binding" pending resolution of the question below. -Do not propagate GO:0033153 "T cell receptor V(D)J recombination" as this is a downstream effect to transcription. Development, specific organs and tissues Neural tissues -Propagate GO:0022008 "neurogenesis" to all vertebrates based on many annotations in all 3 clades. Similarly, propagate GO:0048699 "generation of neurons" to the vertebrates. -Propagate the following to the LEF1 clade only: GO:0021861 forebrain radial glial cell differentiation (from mouse) GO:0021873 forebrain neuroblast division (from mouse) GO:0021879 forebrain neuron differentiation (from Danio) -Propagate GO:0007420 "brain development" to the vertebrates. Propagate GO:0021943 "formation of radial glial scaffolds" to the LEF1 clade from mouse. (This is part of hindbrain development.) -Propagate the following to the LEF1 clade only: GO:0021854 hypothalamus development (from Danio) GO:0021542 dentate gyrus development (from mouse) -Do not propagate GO:0045665 "negative regulation of neuron differentiation" from chicken Lef-1 (PMID 12490564) because the nature of the regulation is not clear. Blood vessels -Propagate the following from mouse (PMID 19154719) to the LEF1 clade: GO:0002040 sprouting angiogenesis GO:0001569 patterning of blood vessels Muscles -Propagate GO:0048747 "muscle fiber development" from fish to LEF1 clade. -Propagate GO:0016202 "regulation of striated muscle tissue development" from mouse to LEF1 clade. (Do not use the "negative" child term.) Other organs and tissues -Propagate the following terms to the LEF1 clade: GO:0048069 "eye pigmentation" from chick GO:0030326 "embryonic limb morphogenesis" from mouse GO:0060325 "face morphogenesis" from mouse. GO:0061153 "trachea gland development" from mouse GO:0030879 "mammary gland development" from mouse GO:0048341 "paraxial mesoderm formation" from mouse GO:0001755 "neural crest cell migration" from fish -Propagate GO:0042475 "odontogenesis of dentine-containing tooth" from mouse to LEF1 clade and note that there are annotations from at least three papers. -Propagate GO:0001837 "epithelial to mesenchymal transition" from mouse and human to LEF1 clade, ignoring "positive regulation" modifier on human. -Propagate GO:0060710 "chorio-allantoic fusion" from mouse to Lef1 clade, but only as far back as chicken (AN6). -Propagate GO:0001756 "somitogenesis" from several mouse and fish annotations to LEF1 clade. -Ignore rat "skin development" annotation from HTP paper PMID 17244330 even though there are annotations in the other 2 vertebrate clades. -Do not propagate the GO:0001822 "kidney development" IEP from rat (PMID 17329570) because it is an in vitro IEP. -Do not propagate GO:0043586 "tongue development" pending resolution of curator question below. -Ignore IEP from rat for GO:0031100 "organ regeneration." -Do not propagate GO:0060033 "anatomical structure regression" from mouse PMID 16163358 as it is secondary to apoptosis and too general a term to propagate based on that. Cellular developmental terms -Propagate the following terms to the LEF1 clade: GO:0046632 "alpha-beta T cell differentiation" from mouse GO:0030223 "neutrophil differentiation" from human GO:0042100 "B cell proliferation" from mouse GO:0071895 "odontoblast differentiation" from rat GO:0001649 "osteoblast differentiation" from human GO:0071864 "positive regulation of cell proliferation in bone marrow" from human Cellular processes other than development Apoptosis -Propagate GO:0060561 "apoptosis involved in morphogenesis" from mouse to LEF1 clade. -Propagate GO:0071866 "negative regulation of apoptosis in bone marrow" from human to LEF1 clade. -Propagate GO:0006917 "induction of apoptosis" from mouse to LEF1 clade. Other cellular processes -Do not propagate "cell chemotaxis" from PMID 19576624 as it is a downstream effect in a tumor cell line. -Propagate GO:0022407 "regulation of cell-cell adhesion" from mouse and human to LEF1 clade, ignoring both positive and negative modifiers. Remaining processes -Do not propagate GO:0014070 "response to organic cyclic compound" IEP from rat. =Questions for MOD curators= ==Molecular Function== ===Human LEF1=== *'''Question: '''Is the IMP to GO:0043027 "caspase inhibitor activity" in PMID 20360943 appropriate? Does the experiment really show a biochemical interaction between LEF1 and caspase, or is reduction of caspase activity a result of mutating LEF1? If the latter, shouldn't that be a BP annotation? **'''Curator answer: '''Insert answer here. *'''Question: '''Does LEF1 really bind estrogen, as the GO:0030284 "estrogen receptor activity" IDA from PMID 18794125 implies? How could LEF1 have both "estrogen receptor activity" and "estrogen receptor binding" activity (from the same paper)? **'''Curator answer: '''Insert answer here. ==Biological Process== ===Mouse Lef1=== * '''Critical''': Should the GO:0043586 "tongue development" annotation from PMID 17284610 , "Wnt signaling interacts with Shh to regulate taste papilla development," be to one of the child terms GO:0061193 "taste bud development" or GO:0061196 "fungiform papilla development"? *Is the annotation to GO:0050909 "sensory perception of taste" from PMID 17284610 really appropriate? The paper describes the role of Lef1 in taste bud development. Isn't taste perception a downstream effect? =Questions for ontology curators= ==Molecular Function== *Based on the definition, shouldn't GO:0003705 "sequence-specific enhancer binding RNA polymerase II transcription factor activity" have some sort of relationship, either is_a or has_part, GO:0035326 "enhancer binding"? ==Biological Process== *The term GO:0071899 "negative regulation of estrogen receptor binding" is defined as "Any process that stops, prevents, or reduces the frequency, rate or extent of estrogen receptor binding, interacting selectively with an estrogen receptor." Binding to what? So, if protein X is annotated to 71899, does it mean that it prevents some other protein Y from binding to the estrogen receptor? If so, should protein Y be listed in the "with" column? Alternatively, does it mean that X prevents the estrogen receptor from binding DNA? Should those two scenarios (binding DNA vs. binding a protein) be separated into new child terms? Is this a general problem with all the "regulation of ___ binding" terms? *What is an appropriate taxonomic restriction for GO:0060710 "chorio-allantoic fusion"? There are annotations out to chicken. *GO:0019083 "viral transcription" is, through a series of intermediates, part_of GO:0016032 "viral reproduction," but there are plenty of example of viral gene transcription that is not directed toward viral reproduction. Genes involved in establishment of latency, for example, are specifically geared towards NOT producing virus particles, so anything involved in transcription of genes involved in establishment of latency should be annotated to 19083 but not 16032. MSL, 10 August 2011 # REFERENCE Annotation inferences using phylogenetic trees The goal of the GO Reference Genome Project, described in PMID 19578431, is to provide accurate, complete and consistent GO annotations for all genes in twelve model organism genomes. To this end, GO curators are annotating evolutionary trees from the PANTHER database with GO terms describing molecular function, biological process and cellular component. GO terms based on experimental data from the scientific literature are used to annotate ancestral genes in the phylogenetic tree by sequence similarity (ISS), and unannotated descendants of these ancestral genes are inferred to have inherited these same GO annotations by descent. The annotations are done using a tool called PAINT (Phylogenetic Annotation and INference Tool).