Gene Report

Basic Information

Approved Symbol	HDAC2
Approved Name	histone deacetylase 2
Symbol Alias	RPD3, YAF1
Location	6q21
Position	chr6:114292073-114292359 (-)
External Links	Entrez Gene: 3066 Ensembl: ENSG00000196591 UCSC: uc003pwd.2 HGNC ID: 4853
No. of Studies (Positive/Negative)	1(1/0)
Type	Literature-origin

Positive relationships between HDAC2 and MDD (count: 1)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
histone deacetylase 2	Hobara, 2010	patients and normal controls		In MDD, the expression of HDAC2 and -5 mRNA was increased in...... In MDD, the expression of HDAC2 and -5 mRNA was increased in a depressive state, but not in a remissive state, compared to controls. More...

Positive relationships between HDAC2 and other components at different levels (count: 0)

Positive relationship network of HDAC2 in MK4MDD

Network loading ...

Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between HDAC2 and MDD (count: 0)

Negative relationships between HDAC2 and other components at different levels (count: 0)

HDAC2 related SNPs in MK4MDD (count: 0)

HDAC2 related proteins in MK4MDD (count: 0)

HDAC2 related GO terms (count: 81)

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0010977	negative regulation of neuron projection development	biological process	ISS[18754010]
GO:0033558	protein deacetylase activity	molecular function	IMP[19041327]
GO:0035098	ESC/E(Z) complex	cellular component	IDA[20075857]
GO:0045347	negative regulation of MHC class II biosynthetic process	biological process	IC[19041327]
GO:0048714	positive regulation of oligodendrocyte differentiation	biological process	IEA
GO:0008134	transcription factor binding	molecular function	IPI[17827154]
GO:0032967	positive regulation of collagen biosynthetic process	biological process	IC[19041327]
GO:0034605	cellular response to heat	biological process	IEA
GO:0006344	maintenance of chromatin silencing	biological process	IMP[19372552]
GO:0016575	histone deacetylation	biological process	IMP[19372552]
GO:0032041	NAD-dependent histone deacetylase activity (H3-K14 specific)	molecular function	IEA
GO:0042220	response to cocaine	biological process	IEA
GO:0045814	negative regulation of gene expression, epigenetic	biological process	TAS
GO:0045944	positive regulation of transcription from RNA polymerase II promoter	biological process	IMP[19041327\|19372552]
GO:0016358	dendrite development	biological process	ISS
GO:0005634	nucleus	cellular component	IDA[18347167\|24970816]
GO:0070932	histone H3 deacetylation	biological process	ISS
GO:0060789	hair follicle placode formation	biological process	ISS[21093383]
GO:0032496	response to lipopolysaccharide	biological process	IEA
GO:0010467	gene expression	biological process	TAS
GO:0016580	Sin3 complex	cellular component	IDA[14966270\|17827154]
GO:0070301	cellular response to hydrogen peroxide	biological process	IEA
GO:0035094	response to nicotine	biological process	IEA
GO:0001047	core promoter binding	molecular function	IEA
GO:0048011	neurotrophin TRK receptor signaling pathway	biological process	TAS
GO:0006351	transcription, DNA-templated	biological process	IEA
GO:0045862	positive regulation of proteolysis	biological process	IMP[19041327]
GO:0005737	cytoplasm	cellular component	IDA[24970816]; TAS[12711221]
GO:0061000	negative regulation of dendritic spine development	biological process	IEA
GO:0061198	fungiform papilla formation	biological process	ISS[21093383]
GO:0045893	positive regulation of transcription, DNA-templated	biological process	IC[19041327]
GO:0070933	histone H4 deacetylation	biological process	ISS
GO:0042475	odontogenesis of dentin-containing tooth	biological process	ISS[21093383]
GO:0042493	response to drug	biological process	IEA
GO:0032922	circadian regulation of gene expression	biological process	ISS
GO:0016581	NuRD complex	cellular component	IDA[17827154\|19644445]
GO:0019899	enzyme binding	molecular function	IPI[11062478\|11641274]
GO:0042517	positive regulation of tyrosine phosphorylation of Stat3 protein	biological process	IEA
GO:0045892	negative regulation of transcription, DNA-templated	biological process	IC[19041327]; IMP[19276356]
GO:2000757	negative regulation of peptidyl-lysine acetylation	biological process	IEA
GO:0071560	cellular response to transforming growth factor beta stimulus	biological process	IEA
GO:0042733	embryonic digit morphogenesis	biological process	ISS[21093383]
GO:0043066	negative regulation of apoptotic process	biological process	ISS[21093383]
GO:0000122	negative regulation of transcription from RNA polymerase II promoter	biological process	IMP[19041327\|19276356]
GO:0010870	positive regulation of receptor biosynthetic process	biological process	IMP[18316616]
GO:0043565	sequence-specific DNA binding	molecular function	IDA[19276356]
GO:0031000	response to caffeine	biological process	IEA
GO:0044822	poly(A) RNA binding	molecular function	IDA[22681889]
GO:0000978	RNA polymerase II core promoter proximal region sequence-specific DNA binding	molecular function	IDA[16217013]
GO:0045786	negative regulation of cell cycle	biological process	TAS
GO:0055093	response to hyperoxia	biological process	IEA
GO:0000790	nuclear chromatin	cellular component	IDA[16217013]
GO:0006338	chromatin remodeling	biological process	IC[17827154]
GO:0032760	positive regulation of tumor necrosis factor production	biological process	IEA
GO:0071300	cellular response to retinoic acid	biological process	IEA
GO:0000980	RNA polymerase II distal enhancer sequence-specific DNA binding	molecular function	IDA[16217013]
GO:0040029	regulation of gene expression, epigenetic	biological process	TAS
GO:0019213	deacetylase activity	molecular function	ISS
GO:0043044	ATP-dependent chromatin remodeling	biological process	IDA[16217013]
GO:0001103	RNA polymerase II repressing transcription factor binding	molecular function	IPI[22926524]
GO:0032732	positive regulation of interleukin-1 production	biological process	IEA
GO:0031492	nucleosomal DNA binding	molecular function	IDA[16217013]
GO:0006325	chromatin organization	biological process	TAS
GO:0004407	histone deacetylase activity	molecular function	IDA[16642021]
GO:0010718	positive regulation of epithelial to mesenchymal transition	biological process	IEA
GO:0043433	negative regulation of sequence-specific DNA binding transcription factor activity	biological process	IMP[19041327]
GO:1903351	cellular response to dopamine	biological process	IEA
GO:0003682	chromatin binding	molecular function	ISS
GO:0003300	cardiac muscle hypertrophy	biological process	IEA
GO:0007596	blood coagulation	biological process	TAS
GO:0051059	NF-kappaB binding	molecular function	IPI[17785205]
GO:0009913	epidermal cell differentiation	biological process	ISS[21093383]
GO:0005654	nucleoplasm	cellular component	TAS
GO:0061029	eyelid development in camera-type eye	biological process	ISS[21093383]
GO:0048149	behavioral response to ethanol	biological process	IEA
GO:0031072	heat shock protein binding	molecular function	IEA
GO:0005515	protein binding	molecular function	IPI[9150135\|11062478\|11259576\|11641274\|11739383\|12140263\|12176973\|12670868\|12711603\|14752048\|16254079\|16464847\|16595694\|16919237\|17245431\|17314511\|17318229\|17827154\|17984088\|18451879\|19182791\|19343227\|19497860\|19505873\|19703393\|19805145\|20195357\|20398657\|
GO:0001975	response to amphetamine	biological process	IEA
GO:0043392	negative regulation of DNA binding	biological process	IEA
GO:0043234	protein complex	cellular component	IDA[16217013]
GO:0008284	positive regulation of cell proliferation	biological process	IMP[18347167]

HDAC2 related KEGG pathways (count: 5)

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa04110	cell cycle	Cell cycle	Mitotic cell cycle progression is accomplished through a rep...... Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. Cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. Downstream targets of CDKs include transcription factor E2F and its regulator Rb. Precise activation and inactivation of CDKs at specific points in the cell cycle are required for orderly cell division. Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated. Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 tumor suppressor protein. p53 and its transcriptional targets play an important role in both G1 and G2 checkpoints. ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation. More...
hsa05200	pathways in_cancer	Pathways in cancer
hsa04330	notch signaling_pathway	Notch signaling pathway	The Notch signaling pathway is an evolutionarily conserved, ...... The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch proteins (Notch1-Notch4 in vertebrates) are single-pass receptors that are activated by the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. They are transported to the plasma membrane as cleaved, but otherwise intact polypeptides. Interaction with ligand leads to two additional proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes. More...
hsa05016	huntingtons disease	Huntington's disease	Huntington disease (HD) is an autosomal-dominant neurodegene...... Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by a CAG repeat expansion in the IT15 gene, which results in a long stretch of polyglutamine close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. In the cytoplasm, full-length mHtt can interfere with BDNF vesicular transport on microtubules. This mutant protein also may lead to abnormal endocytosis and secretion in neurons, because normal Htt form a complex with the proteins Hip1, clathrin and AP2 that are involved in endocytosis. In addition, mHtt affects Ca2+ signaling by sensitizing InsP3R1 to activation by InsP3, stimulating NR2B/NR1 NMDAR activity, and destabilizing mitochondrial Ca2+ handling. As a result, stimulation of glutamate receptors leads to supranormal Ca2+ responses in HD MSN and mitochondrial Ca2+ overload. The mHtt translocates to the nucleus, where it forms intranuclear inclusions, though they are not primarily responsible for toxicity. Nuclear toxicity is believed to be caused by interference with gene transcription, leading to loss of transcription of neuroprotective molecules such as BDNF. While mHtt binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity. Augmented p53 mediates mitochondrial dysfunction. More...
hsa05220	chronic myeloid_leukemia	Chronic myeloid leukemia	Chronic myelogenous leukaemia (CML) is a biphasic disease, i...... Chronic myelogenous leukaemia (CML) is a biphasic disease, initiated by expression of the BCR/ABL fusion gene product in self-renewing, haematopoietic stem cells (HSCs). HSCs can differentiate into common myeloid progenitors (CMPs), which then differentiate into granulocyte/macrophage progenitors (GMPs). HSCs can also differentiate into common lymphoid progenitors (CLPs), which are the progenitors of lymphocytes such as T cells and B cells. The initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic-cell series. Acquisition of additional genetic mutations beyond expression of BCR/ABL causes the progression of CML from chronic phase to blast phase (CML-BP), characterized by an accumulation of myeloid or lymphoid blast cells. The BCR/ABL fusion gene encodes p210BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. The tyrosine kinase activity is essential for cell transformation and the cytoplasmic localization of BCR/ABL allows the assembly of phosphorylated substrates in multiprotein complexes that transmit mitogenic and antiapoptotic signals. Additional cytogenetic and molecular changes are frequently found in patients with CML during the progression of the disease from chronic to blast phase. Some of the genetic changes include mutations in TP53, RB, and CDKN2A (also known as p16INK4A), or overexpression of genes such as EVI1. Additional chromosome translocations are also observed, such as t(3;21)(q26;q22), which generates AML1/EVI1. AML1/EVI-1 represses TGF-beta-mediated growth inhibitory signal. More...

HDAC2 related BioCarta pathways (count: 3)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
ETS_PATHWAY	ets pathway	METS affect on Macrophage Differentiation	Terminal differentiation of cells is often accompanied by re...... Terminal differentiation of cells is often accompanied by repression of cellular proliferation, suggesting that there is a mechanism by which these cellular functions are coordinated. Macrophage differentiation is one model system in which this occurs; as macrophages differentiate, they also stop proliferating. Transcriptional regulation plays a key role in cell cycle progression as well as many differentiation processes. Ras stimulates cell cycle progression in part through Ets transcription factors that bind to cell cycle regulatory genes to activate their expression. Ets transcription factors also help to induce early macrophage differentiation. The activation of Ras signaling by M-CSF activates transcription of genes involved in differentiation through the coordinate expression of both Ets factors and AP-1. Other genes involved in cell cycle regulation involved the coordinate action of E2F-1 and Ets transcription factors. Mets is a factor related in sequence to Ets2 that is upregulated during macrophage differentiation. Increased expression of the Mets protein during macrophage differentiation allows the creation of heterodimers with DP103 to act as transcriptional repressors of cell cycle progression genes, recruiting corepressor to promoters they interact with. DP103 is a gene previously identified as an RNA helicase involved in RNA processing that interacts with EBNA factors from Epstein Barr Virus. The transcriptional repression involving Mets with DP103 is selective, and does not involve all Ets regulated genes. While cell cycle genes are repressed by Mets, other gene activated by Ets factors such as those involved in differentiation are not repressed by Mets. The transcriptional repression by Mets also involved members of the Rb family of tumor suppressors, such as p107 and p130. This requirement for additional factors involved in regulating proliferation may allow for another level of control on cell proliferation and coordination with differentiation. More...
MEF2D_PATHWAY	mef2d pathway	Role of MEF2D in T-cell Apoptosis	Mef2 pathway. Mef2 pathway.
CARM_ER_PATHWAY	carm er_pathway	CARM1 and Regulation of the Estrogen Receptor	Several forms of post-translational modification regulate pr...... Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known. The methylation activity of CARM1 modulates the activity of specific transcriptional regulators. CARM1 acts as a coactivator for the myogenic transcription factor Mef2c, and is necessary for normal muscle cell differentiation. The estrogen receptor is another transcription factor that uses CARM1 as one of several coactivators, acting synergistically with CBP through the Grip1 member of the p160 family of coactivators. The interaction of estrogen receptor with various ligand-dependent coactivators may produce the tissue selective response of some estrogen receptor ligands like tamoxifen. More...

HDAC2 related Reactome pathways (count: 2)

ID	Name	Description
Gene mapped Reactome pathways
REACT_13776	p75 ntr_receptor_mediated_signalling	Besides signalling through the tyrosine kinase receptors TRK...... Besides signalling through the tyrosine kinase receptors TRK A, B, and C, the mature neurotrophins NGF, BDNF, and NT3/4 signal through their common receptor p75NTR. NGF binding to p75NTR activates a number of downstream signalling events controlling survival, death, proliferation, and axonogenesis, according to the cellular context. p75NTR is devoid of enzymatic activity, and signals by recruiting other proteins to its own intracellular domain. p75 interacting proteins include NRIF, TRAF2, 4, and 6, NRAGE, necdin, SC1, NADE, RhoA, Rac, ARMS, RIP2, FAP and PLAIDD. Here we annotate only the proteins for which a clear involvement in p75NTR signalling was demonstrated. A peculiarity of p75NTR is the ability to bind the pro-neurotrophins proNGF and proBDNF. Proneurotrophins do not associate with TRK receptors, whereas they efficiently signal cell death by apoptosis through p75NTR. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75NTR, mediating apoptosis, and mature forms activating TRK receptors, to promote survival. Moreover, the two receptors are utilised to differentially modulate neuronal plasticity. For instance, proBDNF-p75NTR signalling facilitates LTD, long term depression, in the hippocampus , while BDNF-TRKB signalling promotes LTP (long term potentiation). Many biological observations indicate a functional interaction between p75NTR and TRKA signaling pathways. More...
REACT_11061	signalling by_ngf	Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles i...... Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread. Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling. More...

HDAC2 related interactors from protein-protein interaction data in HPRD (count: 65)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
HDAC2	CDH1	No	in vitro	15388328
HDAC2	PA2G4	No	in vitro	12682367
HDAC2	CSNK2A1	Yes	in vitro;in vivo	12176973 , 12082111
HDAC2	BRMS1	No	in vivo	15451426
HDAC2	EED	No	in vitro;in vivo;yeast 2-hybrid	10581039
HDAC2	CDC20	No	in vitro	15388328
HDAC2	CIR1	No	yeast 2-hybrid	9874765
HDAC2	PTMA	No	in vitro	12634383
HDAC2	DNMT1	Yes	in vitro;in vivo;yeast 2-hybrid	10888872
HDAC2	PHF21A	Yes	in vitro	15325272
HDAC2	HDAC1	No	in vitro;in vivo	15451426 , 9520398 , 11287668
HDAC2	SMARCA5	No	in vivo	15775975
HDAC2	MTA1	No	in vitro;in vivo	11146623
HDAC2	SNW1	No	in vitro;in vivo;yeast 2-hybrid	10644367
HDAC2	RFX5	No	in vivo	16464847
HDAC2	CTBP1	No	in vitro;in vivo	10766745 , 11022042
HDAC2	ING1	No	in vivo	15451426
HDAC2	CSNK2A2	No	in vitro	12082111
HDAC2	SIN3A	No	in vitro;in vivo	9150134 , 15451426 , 16254079
HDAC2	TP53	No	in vitro;in vivo	10777477
HDAC2	THRB	No	in vitro	10508171
HDAC2	RBP1	No	in vivo	15451426
HDAC2	HDAC10	No	in vivo	11739383
HDAC2	HIF1AN	No	in vitro	11641274
HDAC2	SP3	No	in vivo	12151407
HDAC2	SETDB1	Yes	in vitro;in vivo	12398767
HDAC2	RUNX3	Yes	in vitro;in vivo	15138260
HDAC2	MXD1	Yes	in vivo	9150134
HDAC2	PPARD	No	in vivo	11867749
HDAC2	DNMT3B	Yes	in vitro;in vivo	15120635
HDAC2	BUB3	No	in vitro	15388328
HDAC2	SP1	No	in vivo	12151407
HDAC2	SUV39H1	No	in vitro;in vivo	11788710
HDAC2	PHB2	No	in vitro	15140878
HDAC2	ARID4A	No	in vivo	10490602
HDAC2	MAD1L1	No	in vitro	15388328
HDAC2	SALL1	No	in vitro	11836251
HDAC2	RBBP7	No	in vivo	15451426
HDAC2	IKZF4	No	in vivo	12015313
HDAC2	TOP2A	No	in vivo	11062478
HDAC2	BRCA1	No	in vitro;in vivo	10220405
HDAC2	BRMS1L	No	in vivo	15451426
HDAC2	IFRD1	No	in vitro;in vivo	12198164
HDAC2	HOPX	Yes	in vivo	12975471
HDAC2	SMYD1	No	in vivo	11923873
HDAC2	NRIP1	No	in vitro	15060175
HDAC2	DAXX	No	in vitro	10669754
HDAC2	THRA	Yes	in vitro	10508171
HDAC2	RELA	No	in vitro;in vivo	12138131 , 12419806
HDAC2	PPP1R8	No	in vitro;in vivo	12788942
HDAC2	RCOR1	No	in vitro;in vivo	11171972
HDAC2	DDX20	No	in vivo	12007404
HDAC2	IKZF1	No	in vitro;in vivo	10357820
HDAC2	DMAP1	No	in vivo;yeast 2-hybrid	10888872
HDAC2	MBD2	No	in vitro;in vivo	10471499
HDAC2	ANTXR1	No	in vivo	10545197
HDAC2	CDYL	No	in vitro;in vivo	12947414
HDAC2	FKBP3	No	in vitro;in vivo	11532945
HDAC2	YY1	No	in vitro;in vivo	11486036
HDAC2	RBBP4	No	in vitro;in vivo	15451426 , 12943729 , 12091390 , 11302704
HDAC2	STAT3	Yes	in vivo	15653507
HDAC2	SAP30	No	in vivo	15451426
HDAC2	SPEN	No	in vitro;in vivo	11331609
HDAC2	PML	No	in vitro	11259576
HDAC2	EID2	No	in vivo	12586827

Gene Report

Gene mapped GO terms

Gene mapped KEGG pathways

Gene mapped BioCarta pathways

Gene mapped Reactome pathways