L3MBTL4

Summary

L3MBTL4 (L3MBTL histone methyl-lysine binding protein 4, HGNC:26677) is a protein-coding gene on chromosome 18p11.31, encoding Lethal(3)malignant brain tumor-like protein 4 (Q8NA19). Putative Polycomb group (PcG) protein.

Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in negative regulation of DNA-templated transcription. Predicted to be active in nucleus.

Source: NCBI Gene 91133 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 119 total
• Druggable target: yes
• MANE Select transcript: NM_001330559

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26677
Approved symbol	L3MBTL4
Name	L3MBTL histone methyl-lysine binding protein 4
Location	18p11.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ35936, HsT1031
Ensembl gene	ENSG00000154655
Ensembl biotype	protein_coding
OMIM	617135
Entrez	91133

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 19 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000317931, ENST00000400104, ENST00000400105, ENST00000578677, ENST00000580162, ENST00000581231, ENST00000583054, ENST00000583809, ENST00000898728, ENST00000898729, ENST00000898730, ENST00000898731, ENST00000898732, ENST00000898733, ENST00000898734, ENST00000898735, ENST00000898736, ENST00000898737, ENST00000955912, ENST00000955913, ENST00000955914

RefSeq mRNA: 8 — MANE Select: NM_001330559 NM_001330559, NM_001365765, NM_001365766, NM_001365767, NM_001365768, NM_001365769, NM_001365770, NM_173464

CCDS: CCDS11839, CCDS82238, CCDS92428

Canonical transcript exons

ENST00000317931 — 19 exons

Exon	Start	End
ENSE00001277260	6263947	6264038
ENSE00001277278	5960094	5960156
ENSE00001277286	5969393	5969562
ENSE00001277310	6171828	6171942
ENSE00001277318	6213149	6213259
ENSE00001277327	6237964	6238040
ENSE00001277344	6311554	6311656
ENSE00001367790	6080881	6080951
ENSE00001371222	6241358	6241449
ENSE00001376053	6243294	6243429
ENSE00001380770	6215750	6215835
ENSE00001382375	6138194	6138296
ENSE00001383351	6301903	6301957
ENSE00001384973	6244484	6244588
ENSE00001385114	6093355	6093528
ENSE00001541562	6414801	6414911
ENSE00001541596	6311998	6312056
ENSE00003564155	6239718	6239872
ENSE00003901253	5954717	5956387

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 92.00.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6649 / max 71.9594, expressed in 756 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171135	1.9644	686
171134	0.4788	259
171132	0.1310	41
171133	0.0908	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	92.00	gold quality
kidney epithelium	UBERON:0004819	88.06	gold quality
sural nerve	UBERON:0015488	86.16	gold quality
calcaneal tendon	UBERON:0003701	83.91	gold quality
epithelial cell of pancreas	CL:0000083	82.41	gold quality
right testis	UBERON:0004534	81.27	gold quality
left testis	UBERON:0004533	80.88	gold quality
testis	UBERON:0000473	80.22	gold quality
right lobe of liver	UBERON:0001114	79.38	gold quality
corpus callosum	UBERON:0002336	79.21	gold quality
liver	UBERON:0002107	78.23	gold quality
pancreatic ductal cell	CL:0002079	77.86	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.75	gold quality
skin of abdomen	UBERON:0001416	77.56	gold quality
sperm	CL:0000019	77.19	silver quality
skin of leg	UBERON:0001511	77.02	gold quality
fallopian tube	UBERON:0003889	76.49	gold quality
zone of skin	UBERON:0000014	76.27	gold quality
ventricular zone	UBERON:0003053	76.07	gold quality
right atrium auricular region	UBERON:0006631	76.04	gold quality
ovary	UBERON:0000992	75.97	gold quality
left ovary	UBERON:0002119	75.96	gold quality
right adrenal gland cortex	UBERON:0035827	75.53	gold quality
cardiac atrium	UBERON:0002081	75.46	gold quality
left adrenal gland	UBERON:0001234	75.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.17	gold quality
right adrenal gland	UBERON:0001233	75.06	gold quality
germinal epithelium of ovary	UBERON:0001304	75.03	gold quality
left adrenal gland cortex	UBERON:0035825	74.74	gold quality
ectocervix	UBERON:0012249	74.27	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	65.98
E-ANND-3	yes	5.23
E-GEOD-111727	no	56.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting L3MBTL4, 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-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-137-3P	99.87	74.74	2401

Literature-anchored findings (GeneRIF, showing 2)

• identified L3MBTL4 as a potential tumor suppressor gene of chromosome arm 18p. The gene is targeted by deletion, breakage and mutations and its mRNA is downregulated in breast tumors (PMID:20698951)
• Findings pinpointed L3MBTL4 as a critical contributor to the development and progression of hypertension. (PMID:27480026)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	L3mbtl4	ENSMUSG00000041565
rattus_norvegicus	L3mbtl4	ENSRNOG00000025273
drosophila_melanogaster	l(3)mbt	FBGN0002441
drosophila_melanogaster	Sfmbt	FBGN0032475
caenorhabditis_elegans	lin-61	WBGENE00003041
caenorhabditis_elegans	mbtr-1	WBGENE00021661

Paralogs (18): SCMH1 (ENSG00000010803), MBTD1 (ENSG00000011258), SCML1 (ENSG00000047634), L3MBTL2 (ENSG00000100395), SCML2 (ENSG00000102098), PHC1 (ENSG00000111752), THAP10 (ENSG00000129028), PHC2 (ENSG00000134686), SAMD1 (ENSG00000141858), SCML4 (ENSG00000146285), SFMBT1 (ENSG00000163935), PHC3 (ENSG00000173889), L3MBTL1 (ENSG00000185513), SAMD7 (ENSG00000187033), SAMD11 (ENSG00000187634), SFMBT2 (ENSG00000198879), L3MBTL3 (ENSG00000198945), SAMD13 (ENSG00000203943)

Protein

Protein identifiers

Lethal(3)malignant brain tumor-like protein 4 — Q8NA19 (reviewed: Q8NA19)

All UniProt accessions (5): Q8NA19, F8W9S8, J3KRN7, J3KS41, J3QLK8

UniProt curated annotations — full annotation on UniProt →

Function. Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility.

Subcellular location. Nucleus.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NA19-1	1	yes
Q8NA19-2	2

RefSeq proteins (8): NP_001317488, NP_001352694, NP_001352695, NP_001352696, NP_001352697, NP_001352698, NP_001352699, NP_775735 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR002515	Znf_C2H2C	Repeat
IPR004092	Mbt	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR050548	PcG_chromatin_remod_factors	Family

Pfam: PF00536, PF01530, PF02820

UniProt features (17 total): binding site 4, repeat 3, splice variant 2, sequence variant 2, chain 1, sequence conflict 1, domain 1, zinc finger region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NA19-F1	75.26	0.51

Functional residue map

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

Ligand- & substrate-binding residues (4): 398; 404; 379; 384

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 42 (showing top): DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOMF_CHROMATIN_BINDING, GOMF_HISTONE_BINDING, OLSSON_E2F3_TARGETS_UP, KIM_MYCN_AMPLIFICATION_TARGETS_UP, MEISSNER_NPC_HCP_WITH_H3_UNMETHYLATED, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, GOBP_NEGATIVE_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_METABOLIC_PROCESS, RATTENBACHER_BOUND_BY_CELF1, ZNF423_TARGET_GENES, ZNF618_TARGET_GENES, MIR1277_5P, MIR4795_3P, MIR126_5P, MIR543

GO Biological Process (5): chromatin organization (GO:0006325), negative regulation of DNA-templated transcription (GO:0045892), regulation of DNA-templated transcription (GO:0006355), regulation of macromolecule metabolic process (GO:0060255), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (5): chromatin binding (GO:0003682), zinc ion binding (GO:0008270), histone binding (GO:0042393), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
regulation of metabolic process	2
binding	2
cellular component organization	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
macromolecule metabolic process	1
primary metabolic process	1
transition metal ion binding	1
protein binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

642 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
L3MBTL4	AKAIN1	P0CW23	570
L3MBTL4	ARHGAP28	Q9P2N2	506
L3MBTL4	C22orf39	Q6P5X5	490
L3MBTL4	GATB	O75879	469
L3MBTL4	CCDC102B	Q68D86	462
L3MBTL4	FIBIN	Q8TAL6	454
L3MBTL4	RTTN	Q86VV8	450
L3MBTL4	FOXRED1	Q96CU9	447
L3MBTL4	GPRC5B	Q9NZH0	426
L3MBTL4	ZNF263	O14978	425
L3MBTL4	COQ9	O75208	425
L3MBTL4	TMEM200C	A6NKL6	418
L3MBTL4	RPGRIP1	Q96KN7	408
L3MBTL4	PRELID3A	Q96N28	405
L3MBTL4	VARS1	P26640	405

IntAct

8 interactions, top by confidence:

A	B	Type	Score
L3MBTL3	SAMD13	psi-mi:“MI:0914”(association)	0.640
NINL	L3MBTL4	psi-mi:“MI:0915”(physical association)	0.560
L3MBTL4	NINL	psi-mi:“MI:0915”(physical association)	0.560
L3MBTL4	GAPDHS	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350
L3MBTL4	PSMA7	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): L3MBTL4 (Two-hybrid), L3MBTL3 (Affinity Capture-MS), PDGFC (Affinity Capture-MS), PSMC1 (Affinity Capture-MS), PSMA5 (Affinity Capture-MS), PSMA7 (Affinity Capture-MS), PSMB5 (Affinity Capture-MS), PSMB6 (Affinity Capture-MS), RPL39 (Affinity Capture-MS), L3MBTL4 (Affinity Capture-MS), L3MBTL4 (Two-hybrid), HSF2BP (Two-hybrid), IGLC1 (Affinity Capture-MS), PMM2 (Affinity Capture-MS), YBEY (Affinity Capture-MS)

ESM2 similar proteins: A2A5N8, A7MBB4, B1B1A0, B2KF05, D3ZWK4, E1C2V1, E9Q3T6, O15060, O43283, O70445, O94966, P0C6P5, P97433, Q0P4M4, Q1HKZ5, Q1LVK9, Q2PFD7, Q3UPF5, Q5DW34, Q5FVG2, Q5R8X7, Q5SW75, Q5TKR9, Q60592, Q63553, Q6P0Q8, Q6ZPI0, Q76I76, Q76I79, Q7TNN8, Q7Z2W4, Q80TF6, Q811L6, Q811P8, Q8BLB7, Q8BRB7, Q8BZ21, Q8CHB8, Q8K3Y6, Q8NA19

Diamond homologs: A2A5N8, B1B1A0, D3YUG0, D3YXK1, D3ZWK4, E1C2V1, O02274, O60284, O95251, P39769, P59178, P70047, P70475, P78364, P97500, Q01538, Q05BQ5, Q1JQD9, Q1RNF8, Q29L50, Q32N90, Q3MIF2, Q4V7W5, Q5DTW2, Q5R737, Q5SVQ0, Q5VUG0, Q5VXD3, Q64028, Q6DIN3, Q6P5G3, Q6SPE9, Q6SPF0, Q7Z3H4, Q80TY4, Q810T5, Q8BLB7, Q8C8Y5, Q8CFC2, Q8CHP6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	92
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

5688 predictions. Top by Δscore:

Variant	Effect	Δscore
18:5956385:CTG:C	acceptor_gain	1.0000
18:5969388:CTCA:C	donor_loss	1.0000
18:5969389:TCA:T	donor_loss	1.0000
18:5969390:CACC:C	donor_loss	1.0000
18:5969391:A:AC	donor_gain	1.0000
18:5969391:A:C	donor_loss	1.0000
18:5969392:C:CC	donor_gain	1.0000
18:5969392:C:CT	donor_loss	1.0000
18:5969563:C:CC	acceptor_gain	1.0000
18:6093534:T:C	acceptor_gain	1.0000
18:6093534:T:TC	acceptor_gain	1.0000
18:6093536:G:C	acceptor_gain	1.0000
18:6146379:CGAGA:C	acceptor_gain	1.0000
18:6171820:GTACT:G	donor_loss	1.0000
18:6171821:TAC:T	donor_loss	1.0000
18:6171822:A:AC	donor_gain	1.0000
18:6171822:AC:A	donor_loss	1.0000
18:6171823:C:CC	donor_gain	1.0000
18:6171823:CTC:C	donor_loss	1.0000
18:6171824:TCACG:T	donor_loss	1.0000
18:6171825:CAC:C	donor_loss	1.0000
18:6171826:A:AC	donor_gain	1.0000
18:6171826:ACG:A	donor_gain	1.0000
18:6171826:ACGC:A	donor_loss	1.0000
18:6171827:C:CA	donor_gain	1.0000
18:6171827:CG:C	donor_gain	1.0000
18:6171827:CGC:C	donor_gain	1.0000
18:6171827:CGCT:C	donor_gain	1.0000
18:6171827:CGCTG:C	donor_gain	1.0000
18:6171839:T:TA	donor_gain	1.0000

AlphaMissense

4079 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:6243372:A:G	W128R	0.999
18:6243372:A:T	W128R	0.999
18:6244497:A:G	L104P	0.999
18:5956377:C:T	G572D	0.998
18:6138258:A:G	C379R	0.998
18:6241426:A:G	W162R	0.998
18:6241426:A:T	W162R	0.998
18:6243407:A:G	L116P	0.998
18:6243407:A:T	L116H	0.998
18:6243413:A:G	L114P	0.998
18:6243416:C:G	R113P	0.998
18:6243417:G:T	R113S	0.998
18:6244557:A:G	F84S	0.998
18:5956359:A:G	L578P	0.997
18:5960104:A:G	F565S	0.997
18:5969407:A:G	W543R	0.997
18:5969407:A:T	W543R	0.997
18:6093518:A:G	C404R	0.997
18:6138242:C:G	C384S	0.997
18:6138243:A:T	C384S	0.997
18:6171867:A:G	W353R	0.997
18:6171867:A:T	W353R	0.997
18:6215809:A:G	W271R	0.997
18:6215809:A:T	W271R	0.997
18:6241389:G:T	A174D	0.997
18:6243370:C:A	W128C	0.997
18:6243370:C:G	W128C	0.997
18:6244495:A:G	S105P	0.997
18:6244534:C:G	G92R	0.997
18:5956368:A:G	F575S	0.996

dbSNP variants (sampled 300 via entrez): RS1000005756 (18:6365291 AG>A), RS1000006381 (18:5965902 G>A), RS1000012856 (18:6149557 T>C), RS1000013928 (18:6400583 C>A,T), RS1000021048 (18:6068997 T>C), RS1000028223 (18:6204534 A>G), RS1000043909 (18:6129029 G>A,T), RS1000072019 (18:6162177 A>G), RS1000077898 (18:6033951 A>G), RS1000079451 (18:6322600 C>G,T), RS1000092906 (18:6304321 A>T), RS1000096835 (18:6368135 G>A), RS1000101514 (18:6076954 A>G), RS1000103902 (18:6245969 G>A,C), RS1000104476 (18:5992016 A>G)

Disease associations

OMIM: gene MIM:617135 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): megacolon (MONDO:0001273)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000763_6	Immunoglobulin A	5.000000e-06
GCST002050_3	Sleep time	4.000000e-06
GCST003613_1	Hypertension	6.000000e-09
GCST005171_12	QT interval	3.000000e-06
GCST008821_4	Neurofibrillary tangles	9.000000e-06
GCST009847_10	Hallux valgus	4.000000e-06
GCST010002_134	Refractive error	4.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:0004682	QT interval
EFO:0006797	neurofibrillary tangles measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1287624 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 9 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.08	IC50	8400	nM	CHEMBL2426482

PubChem BioAssay actives

1 with measured affinity, of 80 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4-pyrrolidin-1-ylpiperidin-1-yl)-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl]methanone	771618: Inhibition of L3MBTL4 (unknown origin) after 30 mins by AlphaScreen assay	ic50	8.4000	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	4
Valproic Acid	increases expression, affects expression	4
Cyclosporine	increases expression	2
Aflatoxin B1	affects expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
bisphenol F	decreases methylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, affects methylation, increases methylation	1
ethyl-p-hydroxybenzoate	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Leflunomide	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1
Methapyrilene	increases methylation	1
Selenomethionine	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1286365	Binding	Inhibition of L3MBTL4 by alpha-screening	Identification of non-peptide malignant brain tumor (MBT) repeat antagonists by virtual screening of commercially available compounds. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery