CEBPE

Summary

CEBPE (CCAAT enhancer binding protein epsilon, HGNC:1836) is a protein-coding gene on chromosome 14q11.2, encoding CCAAT/enhancer-binding protein epsilon (Q15744). Transcriptional activator.

The protein encoded by this gene is a bZIP transcription factor which can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related protein CEBP-delta. The encoded protein may be essential for terminal differentiation and functional maturation of committed granulocyte progenitor cells. Mutations in this gene have been associated with Specific Granule Deficiency, a rare congenital disorder. Multiple variants of this gene have been described, but the full-length nature of only one has been determined.

Source: NCBI Gene 1053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): specific granule deficiency 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 49
• Clinical variants (ClinVar): 250 total — 9 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 23
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Transcription factor: yes — 37 downstream targets (CollecTRI)
• MANE Select transcript: NM_001805

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1836
Approved symbol	CEBPE
Name	CCAAT enhancer binding protein epsilon
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	CRP1
Ensembl gene	ENSG00000092067
Ensembl biotype	protein_coding
OMIM	600749
Entrez	1053

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000206513, ENST00000696121, ENST00000696122

RefSeq mRNA: 1 — MANE Select: NM_001805 NM_001805

CCDS: CCDS9589

Canonical transcript exons

ENST00000206513 — 2 exons

Exon	Start	End
ENSE00003966072	23117306	23117822
ENSE00003966074	23118582	23119255

Expression profiles

Bgee: expression breadth broad, 99 present calls, max score 87.29.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4425 / max 185.9293, expressed in 48 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142317	0.1453	23
142315	0.1373	25
142316	0.1233	17
142318	0.0366	9

Top tissues by expression

244 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bone marrow	UBERON:0002371	87.29	gold quality
bone element	UBERON:0001474	85.00	gold quality
trabecular bone tissue	UBERON:0002483	84.69	gold quality
bone marrow cell	CL:0002092	83.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.00	gold quality
blood	UBERON:0000178	79.91	gold quality
triceps brachii	UBERON:0001509	78.47	gold quality
gluteal muscle	UBERON:0002000	78.20	gold quality
monocyte	CL:0000576	75.92	gold quality
mononuclear cell	CL:0000842	75.54	gold quality
leukocyte	CL:0000738	75.36	gold quality
pancreatic ductal cell	CL:0002079	74.14	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.62	gold quality
granulocyte	CL:0000094	73.37	gold quality
buccal mucosa cell	CL:0002336	72.12	gold quality
vena cava	UBERON:0004087	71.63	silver quality
parotid gland	UBERON:0001831	71.29	gold quality
vastus lateralis	UBERON:0001379	69.40	gold quality
medial globus pallidus	UBERON:0002477	69.32	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	69.13	gold quality
globus pallidus	UBERON:0001875	68.81	gold quality
quadriceps femoris	UBERON:0001377	68.49	gold quality
biceps brachii	UBERON:0001507	67.56	gold quality
oocyte	CL:0000023	66.90	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	66.89	gold quality
body of tongue	UBERON:0011876	66.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	66.75	gold quality
inferior olivary complex	UBERON:0002127	66.74	gold quality
tendon of biceps brachii	UBERON:0008188	66.51	gold quality
lateral globus pallidus	UBERON:0002476	66.43	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	12.88
E-MTAB-9801	yes	7.31
E-ANND-3	yes	3.74

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

37 targets.

Target	Regulation
ATF4
BPI
CAMP	Activation
CDKN1B
CEBPE
CSF3R	Activation
CTSG	Unknown
DDIT4	Activation
EGF
ELANE	Activation
EP300	Unknown
GATA1	Repression
GFI1
GPX4
HP	Activation
LBR
LCN2	Activation
LRG1	Unknown
LTF	Unknown
MMP2	Unknown
MMP8	Activation
MPO
MYC	Repression
NPPA
ORM1	Activation
PER2	Activation
PIK3CG
PRG2	Repression
RETN	Repression
S100A8

JASPAR motifs

Motif	Name	Family
MA0837.1	CEBPE	CEBP-related
MA0837.2	CEBPE	CEBP-related
MA0837.3	CEBPE	CEBP-related

JASPAR matrix evidence (PMIDs): PMID:8632009

Upstream regulators (CollecTRI, top): ATF4, CEBPA, CEBPB, CEBPE, CUX1, MYC, RARA, RXRA, SPI1, STAT1

miRNA regulators (miRDB)

10 targeting CEBPE, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-3157-5P	97.41	67.61	998

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• causative agent in the development of Neutrophil specific granule deficiency (PMID:11753076)
• Conditional expression of C/EBP alpha induced the C/EBP family members C/EBP beta and C/EBP epsilon and subsequent granulocyte differentiation. (PMID:12036869)
• Interacts with other transcription factors to regulate transcription of the gene encoding eosinophil granule major basic protein (PMID:12202480)
• CEBPA and CEBPe repress the leukemic phenotype of acute myeloid leukemia, suppress cell growth, and induce partial differentiation. (PMID:12393450)
• C/EBP epsilon is essential and sufficient for the expression of a particular subset of neutrophil secondary granule genes. (PMID:12515729)
• Upon induction of maturation, C/EBP epsilon binds to the lactoferrin (LF) promoter, which correlates with LF expression. (PMID:12522000)
• overexpression of C/EBPepsilon in myeloid cells leads to down-regulation of c-Myc (PMID:12947005)
• Retinoic acid signaling in granulocytic differentiation involves regulated expression of CHOP protein and C/EBPepsilon in a coordinated fashion. (PMID:15308577)
• CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid and show antitumor activity (PMID:16788101)
• Our data suggest that ATRA-induced regulation of Stat2, ICSBP and C/EBPepsilon is dependent on active Stat1, and that a failure to correctly regulate these transcription factors is associated with the inhibition of monocytic differentiation. (PMID:16918696)
• Decreased Gfi-1 levels in our SGD patient, together with the mutant C/EBPepsilon, block secondary granules proteins expression, thereby contributing to the underlying etiology of the disease in our patient. (PMID:17244686)
• Interaction of the activated NFkappaB pathway and C/EBP-epsilon may be important in selective activation of a subset of C/EBP-epsilon-responsive genes. (PMID:17255362)
• ATF4 may regulate myeloid gene expression differentially by potentiating C/EBPepsilon but inhibiting C/EBPalpha-mediated transcriptional activation. (PMID:17347301)
• the requirement for C/EBP epsilon in mediating BPI gene expression in myeloid cells in vitro and in vivo. (PMID:17483073)
• The type IV isoform of PML interacted with PU.1, promoted its association with p300, and then enhanced PU.1-induced transcription and granulocytic differentiation and PU.1 directly activates the transcription of the C/EBPepsilon gene. (PMID:17562868)
• C/EBP epsilon is a critical transcription factor for tumor necrosis factor alpha-induced up-regulation of phospholipid hydroperoxide glutathione peroxidase (PHGPx) expression in non-differentiated HL60 cells. (PMID:17688422)
• ectopic expression of C/EBPepsilon, as well as C/EBPalpha, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc (PMID:18776924)
• C/EBP- isoforms can reprogram myeloid lineage commitment and differentiation consistent with their predicted activities based on activator and repressor domains and in vitro functional activities (PMID:18832658)
• Substantial quantitities of C-EBPepsilon are expressed in human neutrophils, especially the p14 and p32 variants. (PMID:19109189)
• The results above collectively show that C/EBPepsilon participates in all-trans retinoic acid induction of PI3Kgamma. (PMID:20661648)
• Case provides the first evidence that chromosome duplication and cryptic insertion produce the CEBPE-IGH fusion and that more than one CEBPE-IGH recombination can occur in a leukemic cell. (PMID:22137487)
• Although germ-line SNPs in ARID5B, CEBPE, IKZF1 and CDKN2A are associated with the incidence of ALL in children, authors found no significant association between adult ALL cases and controls. (PMID:23016962)
• rs4132601 in IKZF1 and rs2239633 in CEBPE are not significantly related to childhood childhood acute lymphoblastic leukemia. (PMID:23608171)
• rs2239632 could regulate the expression of the CEBPE gene. Its risk allele (G) might increase the gene product and lead to leukemogenesis. A person with the allele or the corresponding haplotype might have increased susceptibility to ALL. (PMID:23719191)
• study found that previously identified childhood acute lymphoblastic leukemia susceptibility loci in ARID5B and CEBPE show consistent risk effects across both Hispanic and non-Hispanic White populations, providing compelling supportive evidence for susceptibility at these loci (PMID:23836053)
• The expression profiles of transcription factors, C/EBP(alpha, beta, epsilon) and PU.1 were further evaluated in the cells after treatment with ATRA and VPA. (PMID:24379003)
• miR-130a is important for the regulation of the timed expression of C/EBP-epsilon during granulopoiesis. (PMID:24398327)
• Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group. (PMID:24497567)
• Data indicate no significant associations of transcription factors rs4132601 (IKZF1), rs7089424 (ARID5B) and rs2239633 (CEBPE) with risk of pediatric non-Hodgkin lymphoma (NHL). (PMID:25005032)
• Studies indicate that the CCAAT/enhancer binding protein-epsilon (CEBPE) rs2239633 polymorphism was significantly associated with childhood acute lymphoblastic leukemiaacute lymphoblastic leukemia (ALL) risk. (PMID:25195121)
• During neutrophil development, acetylation of lysines 121 and 198 were found to be crucial for terminal neutrophil differentiation and the expression of neutrophil-specific granule proteins, including lactoferrin and collagenase. (PMID:25568349)
• variants within IKZF1, ARID5B, and CEBPE were associated with increased acute lymphoblastic leukemia (ALL) risk, and the effects for ARID5B and CEBPE were most prominent in high-hyperdiploid ALL subtype in the California Hispanic population (PMID:25761407)
• our study provided evidence that CEBPE rs2239633 variant is associated with decreased risk of childhood B-cell ALL in Europeans. (PMID:25938438)
• A novel in-frame deletion in the leucine zipper domain of CEBPE leads to neutrophil-specific granule deficiency. (PMID:26019275)
• CEBPE expression was highest in multipotent progenitor cells (S1) and declined sharply as cells progressed to B-cell-committed progenitors, including pre-B-I cells (S2), pre-B-II cells (S3) and immature B cells (S4) (PMID:26437776)
• variants within IKZF1, ARID5B, and CEBPE were associated with pediatric ALL risks. (PMID:27184773)
• PML/RARalpha synergizes with C/EBPepsilon to reactivate the C/EBPepsilon target G0S2, thereby contributing to All-trans retinoic acid -mediated acute promyelocytic leukemia differentiation and potentially, clinical remission. (PMID:27605212)
• Genotypic and allelic frequencies differed significantly between cases and controls at IKZF1-rs4132601 (p=0.039, p=0.015) and ARID5B-rs10821936 (p=0.028, p=0.026). (PMID:27644650)
• identified the rs45496295 (C > T) polymorphism in the heterozygous state in 73.9% of beta-thalassemia intermedia patients. (PMID:27829304)
• The minor allele of the CEBPE variant associated with lower basophil count has been previously associated with Amerindian ancestry and higher risk of acute lymphoblastic leukemia in Hispanics. (PMID:28158719)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cebp1	ENSDARG00000101096
mus_musculus	Cebpe	ENSMUSG00000052435
rattus_norvegicus	Cebpe	ENSRNOG00000014282
drosophila_melanogaster	slbo	FBGN0005638
caenorhabditis_elegans		WBGENE00016997
caenorhabditis_elegans	zip-4	WBGENE00021552

Paralogs (4): CEBPG (ENSG00000153879), CEBPB (ENSG00000172216), CEBPD (ENSG00000221869), CEBPA (ENSG00000245848)

Protein

Protein identifiers

CCAAT/enhancer-binding protein epsilon — Q15744 (reviewed: Q15744)

All UniProt accessions (1): Q15744

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator. C/EBP are DNA-binding proteins that recognize two different motifs: the CCAAT homology common to many promoters and the enhanced core homology common to many enhancers. Required for the promyelocyte-myelocyte transition in myeloid differentiation.

Subunit / interactions. Binds DNA as a homodimer and as a heterodimer. Can form stable heterodimers with CEBPA, CEBPB and CEBPD. Interacts with GATA1 and SPI1. Interacts with SMARCD2.

Subcellular location. Nucleus.

Tissue specificity. Strongest expression occurs in promyelocyte and late-myeloblast-like cell lines.

Post-translational modifications. Phosphorylated.

Disease relevance. Specific granule deficiency 1 (SGD1) [MIM:245480] An immunologic disorder characterized by recurrent pyogenic infections, defective neutrophil chemotaxis and bactericidal activity, and lack of neutrophil secondary granule proteins. Neutrophils of affected individuals lack lactoferrin and show abnormal nuclear segmentation, bilobed nuclei, low alkaline phosphatase, and increased number of neutrophil mitochondria and ribosomes. SGD1 inheritance can be autosomal dominant or recessive. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 108 with autoinflammation (IMD108) [MIM:260570] An autosomal recessive disorder characterized by autoinflammation and immune impairment of neutrophils, manifesting around adolescence. Affected individuals have recurrent episodes of abdominal pain associated with fever and elevated inflammatory markers. Additional features include recurrent infections, particularly of the skin and nails, poor wound healing, and mild bleeding tendencies. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the bZIP family. C/EBP subfamily.

RefSeq proteins (1): NP_001796* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR016468	C/EBP_chordates	Family
IPR031106	C/EBP	Family
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF07716

UniProt features (16 total): sequence variant 4, sequence conflict 3, region of interest 3, helix 2, chain 1, domain 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3T92	X-RAY DIFFRACTION	1.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15744-F1	64.89	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 181, 121

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 130 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, PARK_TRETINOIN_RESPONSE_AND_RARA_PLZF_FUSION, MODULE_75, MODULE_99, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_LIPID, GOBP_GRANULOCYTE_DIFFERENTIATION, PU1_Q6, RYTTCCTG_ETS2_B

GO Biological Process (12): DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), phagocytosis (GO:0006909), defense response (GO:0006952), positive regulation of gene expression (GO:0010628), myeloid cell differentiation (GO:0030099), macrophage differentiation (GO:0030225), granulocyte differentiation (GO:0030851), positive regulation of transcription by RNA polymerase II (GO:0045944), cellular response to lipopolysaccharide (GO:0071222), integrated stress response signaling (GO:0140467), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
gene expression	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of gene expression	2
myeloid leukocyte differentiation	2
regulation of transcription by RNA polymerase II	2
binding	2
cellular anatomical structure	2
RNA biosynthetic process	1
endocytosis	1
response to stress	1
positive regulation of macromolecule biosynthetic process	1
hemopoiesis	1
cell differentiation	1
mononuclear cell differentiation	1
positive regulation of DNA-templated transcription	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cellular response to stress	1
intracellular signaling cassette	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1380 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CEBPE	ARID5B	Q14865	917
CEBPE	LTF	P02788	863
CEBPE	CENPV	Q7Z7K6	785
CEBPE	SPI1	P17947	784
CEBPE	GATA1	P15976	721
CEBPE	GZMH	P20718	714
CEBPE	PIP4K2A	P48426	670
CEBPE	MPO	P05164	660
CEBPE	RUNX1	Q01196	659
CEBPE	ELANE	P08246	639
CEBPE	IKZF1	Q13422	607
CEBPE	CTSG	P08311	590
CEBPE	GFI1	Q99684	582
CEBPE	CSF3R	Q99062	571
CEBPE	SMARCD2	Q92925	548

IntAct

44 interactions, top by confidence:

A	B	Type	Score
CEBPE	DDIT3	psi-mi:“MI:0407”(direct interaction)	0.590
CEBPE	DDIT3	psi-mi:“MI:0915”(physical association)	0.590
CEBPE	CEBPG	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPA	CEBPE	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	CEBPE	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	CEBPA	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	ATF4	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	ATF3	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	BATF	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	BATF3	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	JUN	psi-mi:“MI:0407”(direct interaction)	0.440
FOS	CEBPE	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	FOSL1	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	ATF5	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	BATF2	psi-mi:“MI:0407”(direct interaction)	0.440
CEBPE	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
CEBPE	DOCK1	psi-mi:“MI:0915”(physical association)	0.400
CCL3L1	CEBPE	psi-mi:“MI:0915”(physical association)	0.370
TNFSF13B	CEBPE	psi-mi:“MI:0915”(physical association)	0.370
CEBPE	MED16	psi-mi:“MI:0915”(physical association)	0.370
CEBPE	DENND4A	psi-mi:“MI:0915”(physical association)	0.370
CEBPE	GTF2A1L	psi-mi:“MI:0915”(physical association)	0.370
CEBPE	ZNF384	psi-mi:“MI:0915”(physical association)	0.370
CEBPE	NELFB	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (72): CEBPE (Affinity Capture-MS), CEBPE (Protein-peptide), CEBPE (Reconstituted Complex), CEBPE (Affinity Capture-RNA), CEBPE (Affinity Capture-MS), CEBPE (Proximity Label-MS), CEBPE (Co-localization), CEBPE (Co-localization), POU2F1 (Two-hybrid), TBX2 (Two-hybrid), TCEB2 (Two-hybrid), MED16 (Two-hybrid), DENND4A (Two-hybrid), GTF2A1L (Two-hybrid), NELFB (Two-hybrid)

ESM2 similar proteins: A1YF56, A2AEV7, A6NCS4, A7Y7W2, D3ZJK7, E1BEA8, F1MUS9, O15534, O35973, O43435, O43638, O60248, O75333, O77728, O94983, O95935, O95947, P22736, P46099, P51666, P56261, P57082, P70325, P70327, Q03484, Q0V8F0, Q15744, Q497V6, Q5DTT2, Q61660, Q61663, Q63HR2, Q64731, Q66JL1, Q6PZD9, Q6ZQN5, Q80Y50, Q810F8, Q861Q9, Q8AV66

Diamond homologs: O02754, O02755, O02756, O77728, P05554, P17676, P21272, P26801, P28033, P49715, P49716, P53566, P53567, P53568, P56261, Q00322, Q02638, Q03484, Q05826, Q15744, Q3T0B9, Q6PZD9, Q9N0J3, Q8IG69, Q02637

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CEBPE	“up-regulates activity”	CEBPG	binding
CEBPE	“up-regulates quantity by expression”	LTF	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Response of EIF2AK1 (HRI) to heme deficiency	5	137.3×	3e-08
Cellular responses to stress	5	7.1×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	10	212.8×	1e-19
transcription by RNA polymerase II	5	10.7×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

250 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	1
Uncertain significance	125
Likely benign	100
Benign	7

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1453726	NM_001805.4(CEBPE):c.201dup (p.Gly68fs)	Pathogenic
1457601	NM_001805.4(CEBPE):c.12_18dup (p.Tyr7fs)	Pathogenic
1705850	NM_001805.4(CEBPE):c.656G>A (p.Arg219His)	Pathogenic
1705852	NM_001805.4(CEBPE):c.742_747del (p.Ser248_Arg249del)	Pathogenic
1705853	NM_001805.4(CEBPE):c.403C>T (p.Arg135Ter)	Pathogenic
1705854	NM_001805.4(CEBPE):c.655_665del (p.Lys220fs)	Pathogenic
530667	NM_001805.4(CEBPE):c.391C>T (p.Arg131Ter)	Pathogenic
8854	NM_001805.4(CEBPE):c.249_253del (p.Asp84fs)	Pathogenic
8855	NM_001805.4(CEBPE):c.509dup (p.Ala171fs)	Pathogenic
982783	NM_001805.4(CEBPE):c.653T>C (p.Val218Ala)	Likely pathogenic

SpliceAI

206 predictions. Top by Δscore:

Variant	Effect	Δscore
14:23118576:TCTTA:T	donor_loss	1.0000
14:23118577:CTTAC:C	donor_loss	1.0000
14:23118578:TTAC:T	donor_loss	1.0000
14:23118579:TA:T	donor_loss	1.0000
14:23118581:C:CG	donor_loss	1.0000
14:23117818:GGGGC:G	acceptor_gain	0.9900
14:23117822:CCTG:C	acceptor_loss	0.9900
14:23117824:T:A	acceptor_loss	0.9900
14:23119391:AAG:A	donor_gain	0.9900
14:23119510:C:CA	donor_gain	0.9900
14:23117823:C:CC	acceptor_gain	0.9700
14:23118580:A:AC	donor_gain	0.9700
14:23118581:C:CC	donor_gain	0.9700
14:23119440:C:CA	donor_gain	0.9700
14:23117747:CCTTG:C	acceptor_gain	0.9600
14:23117819:GGGC:G	acceptor_gain	0.9600
14:23117821:GC:G	acceptor_gain	0.9600
14:23117822:CC:C	acceptor_gain	0.9600
14:23118813:A:C	acceptor_gain	0.9600
14:23118815:G:C	acceptor_gain	0.9600
14:23119411:T:TA	donor_gain	0.9600
14:23117820:GGC:G	acceptor_gain	0.9500
14:23117748:CTTG:C	acceptor_gain	0.9200
14:23117749:TTGT:T	acceptor_gain	0.9200
14:23119439:T:TA	donor_gain	0.9100
14:23118580:AC:A	donor_gain	0.9000
14:23118581:CC:C	donor_gain	0.9000
14:23118813:A:AC	acceptor_gain	0.9000
14:23119412:C:CA	donor_gain	0.8900
14:23117836:C:CT	acceptor_gain	0.8800

AlphaMissense

1806 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:23117554:A:G	L260P	1.000
14:23117563:A:G	L257P	1.000
14:23117575:A:G	L253P	1.000
14:23117596:A:G	L246P	1.000
14:23117655:C:A	K226N	1.000
14:23117655:C:G	K226N	1.000
14:23117660:C:G	A225P	1.000
14:23117661:C:A	K224N	1.000
14:23117661:C:G	K224N	1.000
14:23117663:T:C	K224E	1.000
14:23117668:C:G	R222P	1.000
14:23117670:G:C	S221R	1.000
14:23117670:G:T	S221R	1.000
14:23117672:T:G	S221R	1.000
14:23117673:C:A	K220N	1.000
14:23117673:C:G	K220N	1.000
14:23117675:T:C	K220E	1.000
14:23117677:C:G	R219P	1.000
14:23117678:G:T	R219S	1.000
14:23117680:A:T	V218E	1.000
14:23117683:G:T	A217D	1.000
14:23117684:C:G	A217P	1.000
14:23117688:G:C	N215K	1.000
14:23117688:G:T	N215K	1.000
14:23117689:T:A	N215I	1.000
14:23117690:T:C	N215D	1.000
14:23117691:G:C	N214K	1.000
14:23117691:G:T	N214K	1.000
14:23117692:T:A	N214I	1.000
14:23117692:T:G	N214T	1.000

dbSNP variants (sampled 300 via entrez): RS1001316956 (14:23119458 C>A), RS1001836484 (14:23120512 G>A,C,T), RS1002761409 (14:23121053 G>C), RS1004369475 (14:23119820 T>A), RS1005381410 (14:23121180 C>G,T), RS1007584609 (14:23116898 T>C), RS1007967803 (14:23117313 A>T), RS1008612339 (14:23119713 G>T), RS1008615990 (14:23120182 C>G), RS1008749752 (14:23119154 C>A,G,T), RS1009552277 (14:23119752 AG>A), RS1009893757 (14:23121012 A>G), RS1010763284 (14:23117143 G>A,C), RS1011104096 (14:23117934 A>G), RS1012087007 (14:23116812 G>A)

Disease associations

OMIM: gene MIM:600749 | disease phenotypes: MIM:245480, MIM:260570

GenCC curated gene-disease

Disease	Classification	Inheritance
specific granule deficiency 1	Strong	Autosomal recessive
specific granule deficiency	Supportive	Autosomal recessive

Mondo (3): specific granule deficiency (MONDO:0009506), Pelger-Huet-like anomaly and episodic fever with abdominal pain (MONDO:0009842), specific granule deficiency 1 (MONDO:0044207)

Orphanet (1): Recurrent infections due to specific granule deficiency (Orphanet:169142)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0000421	Epistaxis
HP:0001818	Paronychia
HP:0001954	Recurrent fever
HP:0002027	Abdominal pain
HP:0002718	Recurrent bacterial infections
HP:0002722	Recurrent abscess formation
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0006532	Recurrent pneumonia
HP:0011107	Recurrent aphthous stomatitis
HP:0011447	Hyposegmentation of neutrophil nuclei
HP:0011991	Abnormal total neutrophil count
HP:0011993	Impaired neutrophil bactericidal activity
HP:0012551	Absent neutrophil specific granules
HP:0025708	Early young adult onset
HP:0040238	Impaired neutrophil chemotaxis
HP:0041042	Absent neutrophil lactoferrin
HP:0041043	Neutrophil nuclear clefts
HP:0041044	Low neutrophil alkaline phosphatase
HP:0041045	Increased neutrophil mitochondria
HP:0041046	Increased neutrophil ribosomes

GWAS associations

49 associations (top):

Study	Trait	p-value
GCST000463_2	Acute lymphoblastic leukemia (childhood)	3.000000e-07
GCST001320_15	Acute lymphoblastic leukemia (childhood)	2.000000e-08
GCST001320_20	Acute lymphoblastic leukemia (childhood)	4.000000e-10
GCST001912_3	Acute lymphoblastic leukemia (childhood)	9.000000e-12
GCST002158_5	Acute lymphoblastic leukemia (B-cell precursor)	1.000000e-16
GCST004127_4	White blood cell count (basophil)	6.000000e-06
GCST004600_15	Eosinophil percentage of white cells	8.000000e-09
GCST004600_16	Eosinophil percentage of white cells	4.000000e-29
GCST004606_82	Eosinophil count	1.000000e-32
GCST004608_192	Granulocyte percentage of myeloid white cells	6.000000e-41
GCST004609_208	Monocyte percentage of white cells	1.000000e-12
GCST004609_209	Monocyte percentage of white cells	3.000000e-53
GCST004617_151	Eosinophil percentage of granulocytes	3.000000e-31
GCST004618_38	White blood cell count (basophil)	3.000000e-22
GCST004623_65	Neutrophil percentage of granulocytes	7.000000e-12
GCST004623_66	Neutrophil percentage of granulocytes	2.000000e-37
GCST004624_155	Sum eosinophil basophil counts	1.000000e-11
GCST004624_158	Sum eosinophil basophil counts	2.000000e-38
GCST004625_143	Monocyte count	1.000000e-52
GCST004631_56	Basophil percentage of white cells	6.000000e-28
GCST004631_57	Basophil percentage of white cells	2.000000e-41
GCST004633_31	Neutrophil percentage of white cells	4.000000e-09
GCST004634_40	Basophil percentage of granulocytes	5.000000e-27
GCST004634_41	Basophil percentage of granulocytes	1.000000e-38
GCST005315_8	Acute lymphoblastic leukemia (childhood)	7.000000e-13
GCST005832_11	Acute lymphoblastic leukemia in childhood (B cell precursor)	5.000000e-14
GCST005976_22	White blood cell count (basophil)	6.000000e-21
GCST005977_11	Monocyte count	4.000000e-10
GCST009638_9	B-cell acute lymphoblastic leukaemia	2.000000e-21
GCST90002379_59	Basophil count	3.000000e-14

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005091	monocyte count
EFO:0007992	basophil percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007995	basophil percentage of granulocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564899	Pelger-Huet-Like Anomaly and Episodic Fever with Abdominal Pain (supp.)
C562873	Specific Granule Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases reaction, affects reaction, affects binding, decreases reaction, increases expression (+1 more)	13
Arsenic Trioxide	decreases reaction, increases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
hexamethylene bisacetamide	affects cotreatment, increases expression	1
sulforaphane	increases expression	1
cypermethrin	increases expression, decreases reaction	1
3-phenoxybenzoic acid	decreases reaction, increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
fluorotelomer alcohols	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
caffeic acid phenethyl ester	increases expression, increases reaction	1
tamibarotene	increases expression, increases reaction, decreases expression, decreases reaction	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression, increases reaction	1
pomalidomide	increases expression	1
Leflunomide	decreases expression	1
Acetylcysteine	increases expression, decreases reaction	1
Allergens	increases expression	1
Auranofin	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Butyrates	increases expression, affects cotreatment	1
Diazinon	increases methylation	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Methapyrilene	decreases methylation	1
Methotrexate	decreases expression	1
Ozone	affects expression, increases abundance	1
Aflatoxin B1	decreases methylation	1
Sodium Selenite	increases expression	1
Thapsigargin	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0P9	SEES3-1V human CEBPE, clone1	Embryonic stem cell	Male
CVCL_A0Q0	SEES3-1V human CEBPE, clone2	Embryonic stem cell	Male
CVCL_A0Q1	SEES3-1V human CEBPE, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.