BioPAX pathway converted from "Expression of globin genes under control of the beta globin control region" in the Reactome database. LEFT-TO-RIGHT Expression of globin genes under control of the beta globin control region The human beta-globin locus consists of five genes encoding the beta globin gene but also delta, gamma-A, gamma-G and epsilon globin. All of these genes are controlled by the beta globin locus control region. Authored: Ouwehand, WH, 2010-11-12 Reviewed: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-16 Converted from EntitySet in Reactome Globin genes Reactome DB_ID: 9605269 HBD gene Reactome DB_ID: 9605273 nucleoplasm GENE ONTOLOGY GO:0005654 ENSEMBL:ENSG00000223609 HBD HBD Homo sapiens NCBI Taxonomy 9606 ENSEMBL ENSG00000223609 Reactome Database ID Release 79 9605273 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605273 Reactome R-HSA-9605273 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605273.1 Reactome http://www.reactome.org HBB gene Reactome DB_ID: 8958094 ENSEMBL:ENSG00000244734 HBB HBB ENSEMBL ENSG00000244734 Reactome Database ID Release 79 8958094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8958094 Reactome R-HSA-8958094 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8958094.1 HBG1 gene Reactome DB_ID: 8958511 ENSEMBL:ENSG00000213934 HBG1 HBG1 PRO2979 ENSEMBL ENSG00000213934 Reactome Database ID Release 79 8958511 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8958511 Reactome R-HSA-8958511 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8958511.1 HBG2 gene Reactome DB_ID: 8958286 ENSEMBL:ENSG00000196565 HBG2 HBG2 ENSEMBL ENSG00000196565 Reactome Database ID Release 79 8958286 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8958286 Reactome R-HSA-8958286 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8958286.1 HBE1 gene Reactome DB_ID: 9605272 ENSEMBL:ENSG00000213931 HBE1 HBE1 HBE ENSEMBL ENSG00000213931 Reactome Database ID Release 79 9605272 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605272 Reactome R-HSA-9605272 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605272.1 Reactome Database ID Release 79 9605269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9605269 Reactome R-HSA-9605269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9605269.1 HBG1 Hemoglobin subunit gamma-1 HBG1_HUMAN Reactome DB_ID: 1008211 cytosol GENE ONTOLOGY GO:0005829 UniProt:P69891 HBG1 HBG1 PRO2979 FUNCTION Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.SUBUNIT Heterotetramer of two alpha chains and two gamma chains in fetal hemoglobin (Hb F). In the case of deletions affecting one or more of the alpha chains, the excess gamma chains form homotetramers that exhibit neither Bohr effect nor heme-heme cooperativity (hemoglobin Bart's).TISSUE SPECIFICITY Red blood cells.DEVELOPMENTAL STAGE Expressed until four or five weeks after birth. Detected at very low levels in adults, where it constitutes about 1% of the total hemoglobin. In contrast, the levels of fetal hemoglobin F (two alpha chains and two gamma chains) are increased in children and adults with beta-thalassemia or sickle-cell disease. In cases of homozygous alpha-thalassemia, homotetrameric hemoglobin Bart's is highly expressed and is the predominant form of hemoglobin after 10 weeks of gestation. Its levels increase steadily after 10 weeks of gestation and until birth (at protein level).INDUCTION By 5-azacytidine.PTM Acetylation of Gly-2 converts Hb F to the minor Hb F1.SIMILARITY Belongs to the globin family.CAUTION The modification form of Leu-142 is subject of controversy and could be the artifactual result of sample handling. UniProt P69891 2 EQUAL 147 EQUAL Reactome Database ID Release 79 1008211 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008211 Reactome R-HSA-1008211 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008211.1 HBG2 Hemoglobin subunit gamma-2 HBG2_HUMAN Reactome DB_ID: 1008254 UniProt:P69892 HBG2 HBG2 FUNCTION Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.SUBUNIT Heterotetramer of two alpha chains and two gamma chains in fetal hemoglobin (Hb F).TISSUE SPECIFICITY Red blood cells.DEVELOPMENTAL STAGE Expressed until four or five weeks after birth.PTM Acetylation of Gly-2 converts Hb F to the minor Hb F1.SIMILARITY Belongs to the globin family. UniProt P69892 2 EQUAL 147 EQUAL Reactome Database ID Release 79 1008254 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008254 Reactome R-HSA-1008254 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008254.1 HBD Hemoglobin subunit delta HBD_HUMAN Reactome DB_ID: 1008218 UniProt:P02042 HBD HBD FUNCTION Involved in oxygen transport from the lung to the various peripheral tissues.SUBUNIT Heterotetramer of two alpha chains and two delta chains in adult hemoglobin A2 (HbA2). HbA2 represents less than 3.5% of adult hemoglobin.TISSUE SPECIFICITY Red blood cells.SIMILARITY Belongs to the globin family. UniProt P02042 2 EQUAL 147 EQUAL Reactome Database ID Release 79 1008218 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008218 Reactome R-HSA-1008218 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008218.1 HBE1 Hemoglobin subunit epsilon HBE_HUMAN Reactome DB_ID: 1008215 UniProt:P02100 HBE1 HBE1 HBE FUNCTION The epsilon chain is a beta-type chain of early mammalian embryonic hemoglobin.SUBUNIT Heterotetramer of two alpha chains and two epsilon chains in early embryonic hemoglobin Gower-2; two zeta chains and two epsilon chains in early embryonic hemoglobin Gower-1.TISSUE SPECIFICITY Red blood cells.SIMILARITY Belongs to the globin family. UniProt P02100 2 EQUAL 147 EQUAL Reactome Database ID Release 79 1008215 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008215 Reactome R-HSA-1008215 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008215.1 HBB Hemoglobin subunit beta HBB_HUMAN Reactome DB_ID: 1008196 UniProt:P68871 HBB HBB FUNCTION Involved in oxygen transport from the lung to the various peripheral tissues.FUNCTION LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.SUBUNIT Heterotetramer of two alpha chains and two beta chains in adult hemoglobin A (HbA). Heterotetramer of two zeta chains and two beta chains in hemoglobin Portland-2, detected in fetuses and neonates with homozygous alpha-thalassemia.TISSUE SPECIFICITY Red blood cells.PTM Glucose reacts non-enzymatically with the N-terminus of the beta chain to form a stable ketoamine linkage. This takes place slowly and continuously throughout the 120-day life span of the red blood cell. The rate of glycation is increased in patients with diabetes mellitus.PTM S-nitrosylated; a nitric oxide group is first bound to Fe(2+) and then transferred to Cys-94 to allow capture of O(2).PTM Acetylated on Lys-60, Lys-83 and Lys-145 upon aspirin exposure.POLYMORPHISM Genetic variations in HBB are involved in resistance to malaria [MIM:611162]. Hemoglobin S (Hb S), which at homozygosity is responsible for sickle cell anemia, is not associated with any clinical abnormality when heterozygous. At heterozygosity, Hb S confers an increase in protection from life-threatening malaria. Additional variants conferring resistance against severe malaria are hemoglobin C (Hb C) and hemoglobin E (Hb E).MISCELLANEOUS One molecule of 2,3-bisphosphoglycerate can bind to two beta chains per hemoglobin tetramer.SIMILARITY Belongs to the globin family.CAUTION The modification form of Leu-142 is subject of controversy and could be the artifactual result of sample handling.CAUTION It is unclear if hemoglobin Beckman (Hb Beckman) is defined by p.Ala136Glu or p.Ala136Asp. Hb Beckman has been originally identified by reverse phase-HPLC and tandem mass spectrometry, and has been reported as variant p.Ala136Glu (Ref.140). Subsequently, variant p.Ala136Asp has been reported based on HBB gene complete sequencing results (PubMed:19453576). Variant p.Ala136Asp has also been detected by mass spectrometry (PubMed:26209877). Although the name Hb Beckman is currently used for variant p.Ala136Asp, it cannot be ruled out that Hb Beckman is indeed variant p.Ala136Glu (PubMed:19453576). UniProt P68871 2 EQUAL 147 EQUAL Reactome Database ID Release 79 1008196 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008196 Reactome R-HSA-1008196 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008196.1 Reactome Database ID Release 79 1008220 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008220 Reactome R-HSA-1008220 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008220.3 11895428 Pubmed 2002 The human beta-globin locus control region Levings, PP Bungert, J Eur J Biochem 269:1589-99 2649166 Pubmed 1989 A review of the molecular genetics of the human alpha-globin gene cluster Higgs, DR Vickers, MA Wilkie, AO Pretorius, IM Jarman, AP Weatherall, DJ Blood 73:1081-104 ACTIVATION Reactome Database ID Release 79 1015871 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1015871 Reactome R-HSA-1015871 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1015871.1 NF-E2:Promoter region of beta-globin Reactome DB_ID: 1008206 Promotor region of beta-globin Reactome DB_ID: 1008228 Reactome Database ID Release 79 1008228 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008228 Reactome R-ALL-1008228 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1008228.2 ChEBI 61120 additional information MI MI:0361 1 NF-E2 Reactome DB_ID: 1008229 Converted from EntitySet in Reactome Small Maf family members Reactome DB_ID: 1008234 MAFF Transcription factor MAFF MAFF_HUMAN Reactome DB_ID: 1008261 UniProt:Q9ULX9 MAFF MAFF FUNCTION Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (PubMed:8932385). However, they seem to serve as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins, such as NFE2L1/NRF1, and recruiting them to specific DNA-binding sites. Interacts with the upstream promoter region of the oxytocin receptor gene (PubMed:8932385, PubMed:16549056). May be a transcriptional enhancer in the up-regulation of the oxytocin receptor gene at parturition (PubMed:10527846).SUBUNIT Monomer and homo- or heterodimer. Interacts with MIP (PubMed:16549056). Forms high affinity heterodimers with members of the CNC-bZIP family such as NFE2L1/NRF1 (PubMed:8932385).TISSUE SPECIFICITY Expressed in the term myometrium and kidney.INDUCTION By oxidative stress.SIMILARITY Belongs to the bZIP family. Maf subfamily. UniProt Q9ULX9 1 EQUAL 164 EQUAL Reactome Database ID Release 79 1008261 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008261 Reactome R-HSA-1008261 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008261.1 MAFG Transcription factor MAFG MAFG_HUMAN Reactome DB_ID: 1008212 UniProt:O15525 MAFG MAFG FUNCTION Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (PubMed:11154691). However, they seem to serve as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins, such as NFE2, NFE2L1 and NFE2L2, and recruiting them to specific DNA-binding sites (PubMed:8932385, PubMed:9421508, PubMed:11154691). Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NFE2L2 transcription factor (PubMed:11154691). Transcription factor, component of erythroid-specific transcription factor NFE2L2 (PubMed:11154691). Activates globin gene expression when associated with NFE2L2 (PubMed:11154691). May be involved in signal transduction of extracellular H(+) (By similarity).SUBUNIT Homodimer or heterodimer. Homodimerization leads to transcriptional repression. Forms high affinity heterodimers with members of the CNC-bZIP family such as NFE2, NFE2L1/NRF1, NFE2L2/NRF2 and NFE2L3/NRF3 (PubMed:8932385, PubMed:9421508, PubMed:11154691). Interacts with CREBBP; the interaction leads to acetylation of the basic region of MAFG and stimulation of NFE2 transcriptional activity through increased DNA binding.TISSUE SPECIFICITY Highly expressed in skeletal muscle. Also expressed in heart and brain.PTM Acetylated in erythroid cells by CREB-binding protein (CBP). Acetylation augments the DNA-binding activity of NFE2, but has no effect on binding NFE2.PTM Sumoylation at Lys-14 is required for active transcriptional repression.SIMILARITY Belongs to the bZIP family. Maf subfamily. UniProt O15525 1 EQUAL 162 EQUAL Reactome Database ID Release 79 1008212 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008212 Reactome R-HSA-1008212 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008212.1 MAFK Transcription factor MAFK MAFK_HUMAN Reactome DB_ID: 1008242 UniProt:O60675 MAFK MAFK FUNCTION Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (PubMed:9150357). However, they act as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins, such as NFE2, NFE2L1/NRF1, NFE2L2/NRF2 and NFE2L3/NRF3, and recruiting them to specific DNA-binding sites (PubMed:9150357, PubMed:8932385). Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NF-E2 transcription factor (PubMed:9150357).SUBUNIT Homodimer or heterodimer. It can form high affinity heterodimers with members of the CNC-bZIP family such as NFE2, NFE2L1/NRF1, NFE2L2/NRF2 and NFE2L3/NRF3 (PubMed:9150357, PubMed:8932385).SIMILARITY Belongs to the bZIP family. Maf subfamily. UniProt O60675 1 EQUAL 156 EQUAL Reactome Database ID Release 79 1008242 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008242 Reactome R-HSA-1008242 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008242.1 Reactome Database ID Release 79 1008234 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008234 Reactome R-HSA-1008234 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008234.1 1 NFE2 Transcription factor NF-E2 45 kDa subunit p45 NF-E2 NFE2_HUMAN Reactome DB_ID: 1008221 UniProt:Q16621 NFE2 NFE2 FUNCTION Component of the NF-E2 complex essential for regulating erythroid and megakaryocytic maturation and differentiation. Binds to the hypersensitive site 2 (HS2) of the beta-globin control region (LCR). This subunit (NFE2) recognizes the TCAT/C sequence of the AP-1-like core palindrome present in a number of erythroid and megakaryocytic gene promoters. Requires MAFK or other small MAF proteins for binding to the NF-E2 motif. May play a role in all aspects of hemoglobin production from globin and heme synthesis to procurement of iron.SUBUNIT Homodimer; can bind DNA as a homodimer. Erythroid transcription activator nuclear factor erythroid-derived 2 (NF-E2), composed of a heterodimer of NFE2 and MAFK, possesses transactivation activity on beta-globin. Also forms high affinity heterodimer with MAFG; the interaction promotes erythropoiesis. Interacts (via the PXY motif 1) with ITCH (via the WW 1 domain); the interaction promotes 'Lys63'-linked ubiquitination of NFE2, translocates it to the cytoplasm and inhibits its transactivation activity. Interacts with KMT2D/MLL2; the interaction promotes transactivation of the beta-globin locus (By similarity). Interacts with MAPK8 (phosphorylated form); the interaction leads to phosphorylation of NFE2 in undifferentiated cells (By similarity).TISSUE SPECIFICITY Expressed in hematopoietic cells and also in colon and testis.DOMAIN The PXY motifs are required for binding WW domains. PXY1 is required to promote transactivation of beta-globin and for hyperacetylation of histone H3, but not for binding to the HS2 promoter site (By similarity).PTM Phosphorylated on serine residues. In undifferentiated erythrocytes, phosphorylated by MAPK8 which then leads to ubiquitination and protein degradation.PTM Sumoylated. Sumoylation is required for translocation to nuclear bodies PODs, anchoring to the gene loci, and transactivation of the beta-globin gene.PTM Ubiquitinated mainly by 'Lys63'-linked ubiquitin. Polyubiquitination with 'Lys63'-linked ubiquitin by ITCH retains NFE2 in the cytoplasm preventing its transactivation activity. In undifferentiated erythrocyte, ubiquitinated after MAPK8-mediatd phosphorylation leading to protein degradation (By similarity).SIMILARITY Belongs to the bZIP family. CNC subfamily. UniProt Q16621 1 EQUAL 373 EQUAL Reactome Database ID Release 79 1008221 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008221 Reactome R-HSA-1008221 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008221.1 1 Reactome Database ID Release 79 1008229 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008229 Reactome R-HSA-1008229 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008229.1 1 Reactome Database ID Release 79 1008206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1008206 Reactome R-HSA-1008206 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1008206.1