LIN28A

Summary

LIN28A (lin-28 RNA binding posttranscriptional regulator A, HGNC:15986) is a protein-coding gene on chromosome 1p36.11, encoding Protein lin-28 homolog A (Q9H9Z2). RNA-binding protein that inhibits processing of pre-let-7 miRNAs and regulates translation of mRNAs that control developmental timing, pluripotency and metabolism.

This gene encodes a LIN-28 family RNA-binding protein that acts as a posttranscriptional regulator of genes involved in developmental timing and self-renewal in embryonic stem cells. The encoded protein functions through direct interaction with target mRNAs and by disrupting the maturation of certain miRNAs involved in embryonic development. This protein prevents the terminal processing of the LET7 family of microRNAs which are major regulators of cellular growth and differentiation. Aberrant expression of this gene is associated with cancer progression in multiple tissues.

Source: NCBI Gene 79727 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 29 total
• Druggable target: yes
• MANE Select transcript: NM_024674

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15986
Approved symbol	LIN28A
Name	lin-28 RNA binding posttranscriptional regulator A
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	LIN-28, FLJ12457, ZCCHC1, CSDD1
Ensembl gene	ENSG00000131914
Ensembl biotype	protein_coding
OMIM	611043
Entrez	79727

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000254231, ENST00000326279

RefSeq mRNA: 1 — MANE Select: NM_024674 NM_024674

CCDS: CCDS280

Canonical transcript exons

ENST00000326279 — 4 exons

Exon	Start	End
ENSE00000902185	26425303	26425487
ENSE00000902186	26411386	26411582
ENSE00001038111	26410817	26410922
ENSE00001462759	26426242	26429728

Expression profiles

Bgee: expression breadth broad, 26 present calls, max score 91.00.

FANTOM5 (CAGE): breadth broad, TPM avg 33.9990 / max 1685.1797, expressed in 221 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1609	30.4373	206
1607	2.0531	177
1608	0.8458	145
1606	0.4802	139
1610	0.1827	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	91.00	gold quality
secondary oocyte	CL:0000655	90.82	gold quality
sperm	CL:0000019	88.21	gold quality
male germ cell	CL:0000015	84.95	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.33	gold quality
buccal mucosa cell	CL:0002336	80.96	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.83	gold quality
left testis	UBERON:0004533	66.35	gold quality
testis	UBERON:0000473	65.40	gold quality
right testis	UBERON:0004534	64.75	gold quality
sural nerve	UBERON:0015488	57.61	gold quality
embryo	UBERON:0000922	57.22	gold quality
bone marrow cell	CL:0002092	55.36	gold quality
lower lobe of lung	UBERON:0008949	54.35	silver quality
endothelial cell	CL:0000115	53.80	gold quality
adrenal tissue	UBERON:0018303	50.41	silver quality
tibialis anterior	UBERON:0001385	49.97	silver quality
oviduct epithelium	UBERON:0004804	49.71	gold quality
calcaneal tendon	UBERON:0003701	49.56	silver quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
quadriceps femoris	UBERON:0001377	48.93	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
deltoid	UBERON:0001476	48.52	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	333.38
E-MTAB-8271	yes	7.07
E-ANND-3	yes	4.10
E-MTAB-6819	no	681.11

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CCND1	Unknown
CDC25A	Unknown

Upstream regulators (CollecTRI, top): AR, ASCL1, DACH1, HMGA1, HMGA2, KAT2B, MYC, REST, SIRT1, SOX2, SP1, STAT3, VDR, ZFP42

miRNA regulators (miRDB)

166 targeting LIN28A, 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-4262	100.00	73.26	3931
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-6833-3P	100.00	70.63	3197
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4531	99.99	69.70	3181
HSA-LET-7A-5P	99.98	72.29	1790

Literature-anchored findings (GeneRIF, showing 40)

• microRNA regulation is a conserved feature of the Lin-28 gene in diverse animals. (PMID:12798299)
• Lin-28 downregulation by miR-125 involves reductions in both translational efficiency and mRNA abundance. (PMID:16227573)
• analysis of let-7g microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28 (PMID:18550544)
• LIN-28 does not seem to be involved in the self-renewal of human embryonic stem cells, but rather seems to be involved in their decision to switch from self-renewal to differentiation. (PMID:19038789)
• Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7 (PMID:19153603)
• Study shows that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency approximately 15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. (PMID:19483683)
• overexpression of Lin28 is associated with human germ-cell tumors (PMID:19578360)
• This study uncovers the role of TUT4 and Lin28 as specific suppressors of microRNA biogenesis, which has implications for stem cell research and cancer biology. (PMID:19703396)
• Src activates an inflammatory signal, and epigenetic inheritance is mediated by a positive feedback loop involving the NF-kappaB transcription factor, Lin28, Let-7 microRNA, and IL6; this regulatory circuit links inflammation to cellular transformation. (PMID:19878981)
• Results suggest a role for Lin28 in the regulation of Oct4 translation. (PMID:19966271)
• Lin28 and Oct4 may have important roles in the initiation and/or progression of epithelial ovarian cancer. (PMID:20101213)
• miRNAs let-7, mir-125, mir-9, and mir-30 directly repress LIN28 expression in embryonic stem and cancer cells (PMID:20947512)
• Data suggest that A rebalancing of the LIN28/let-7 regulatory loop could be a novel therapeutic strategy to target ALDH1+ cancer stem cells. (PMID:21045151)
• For primary extragonadal yolk sac tumors, combining LIN28 and SALL4 can achieve a higher diagnostic sensitivity than either alone. (PMID:21057460)
• Of the 16 malignant rhabdoid tumors, 14 (88%) tumors showed robust SALL4 and/or LIN28 expression. (PMID:21417895)
• Lin28, working in concert with RNA Helicase A, enhances the translation of genes important for the growth and survival of human embryonic stem cells. (PMID:21425412)
• induction of Lin-28 could mediate repression of let-7 family members, promote cell cycle progression and suppress cell proliferation (PMID:21553022)
• LIN28 regulates the differentiation status of seminoma and embryonal carcinoma and is likely to play a related role in normal human germ-cell development. (PMID:21631526)
• A conformational change in LIN28 binding is determined that results in the unwinding of an otherwise double-stranded region at the Dicer processing site of pre-let-7g microRNA. (PMID:21815640)
• this study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk. (PMID:21912531)
• let-7 and Lin28 have contrary roles in megakaryocytic (MK) differentiation with a dynamic balance (PMID:21979467)
• LIN28 is a sensitive marker for ovarian germ cell tumours (PMID:22034885)
• These results suggest the possible involvement of LIN28 in regulation of sex steroid dependent cell proliferation of breast carcinoma cells. (PMID:22081076)
• Lin28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. (PMID:22118463)
• Data show that the zinc knuckle domains of Lin28 are sufficient to provide binding selectivity for pre-let-7 miRNAs. (PMID:22157959)
• L1TD1 is part of the L1TD1-RHA-LIN28 complex that could influence levels of OCT4, suggesting that L1TD1 has an important role in the regulation of stemness. (PMID:22162396)
• Lin28 mRNA contains ARE within its 3’-UTR and TTP enhances the decay of Lin28 mRNA through binding to its 3’-UTR. (PMID:22210895)
• LIN28A is strongly expressed in germ cells during early human ovary development, but disruption of LIN28Ais not a common cause of primary ovarian insufficiency. (PMID:22240064)
• Both HeLaS3/pAAV2neo-Lin28a and HeLaS3/pAAV2neo-Lin28b could express Lin28a and Lin28b effectively. (PMID:22263265)
• LIN28 expression is germ cell specific and becomes restricted to a subpopulation of germ cells with increasing gestation in the fetal ovary. (PMID:22296229)
• that LIN28 was a negative independent predictor for both overall survival and recurrence-free survival in hepatocellular carcinoma patients who met the Milan criteria. LIN28 was expressed at a higher frequency in tumor tissues than in non-HCC tissues. (PMID:22429493)
• High expression of Lin28 is associated with poor prognosis and high tumour aggressiveness in oesophageal cancer and these effects are mediated through increased proliferation and invasiveness of oesophageal cancer cells. (PMID:22433967)
• Lin-28 homologue A (LIN28A) promotes cell cycle progression via regulation of cyclin-dependent kinase 2 (CDK2), cyclin D1 (CCND1), and cell division cycle 25 homolog A (CDC25A) expression in cancer. (PMID:22467868)
• findings therefore show a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo (PMID:22532168)
• LIN28 is a predicted target of miR-125b in differentiating human embryonic stem cells. (PMID:22545159)
• LIN28 is expressed only in a very small subpopulation of spermatogonia in the adult monkey and human testis (PMID:22689537)
• Lin28 stimulates HER2 expression at the posttranscriptional level, and that enforced Lin28 expression promotes cancer cell growth via multiple mechanisms. (PMID:22713243)
• Overexpression of Lin28 in breast cancer cells considerably induced p21 and Rb expression and inhibited Let-7 miRNA levels. (PMID:22808086)
• Lin28 uses two different TUTases to control let-7 expression. (PMID:22898984)
• A subset of Lin28 mRNA targets are destabilized in a Drosha-dependent manner. (PMID:22935707)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	lin28aa	ENSDARG00000004328
danio_rerio	lin28ab	ENSDARG00000016999
mus_musculus	Lin28a	ENSMUSG00000050966
rattus_norvegicus	Lin28a	ENSRNOG00000082489
drosophila_melanogaster	lin-28	FBGN0035626
caenorhabditis_elegans	cey-2	WBGENE00000473
caenorhabditis_elegans	cey-3	WBGENE00000474
caenorhabditis_elegans		WBGENE00000475

Paralogs (4): YBX2 (ENSG00000006047), YBX3 (ENSG00000060138), YBX1 (ENSG00000065978), LIN28B (ENSG00000187772)

Protein

Protein identifiers

Protein lin-28 homolog A — Q9H9Z2 (reviewed: Q9H9Z2)

Alternative names: Zinc finger CCHC domain-containing protein 1

All UniProt accessions (1): Q9H9Z2

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein that inhibits processing of pre-let-7 miRNAs and regulates translation of mRNAs that control developmental timing, pluripotency and metabolism. Seems to recognize a common structural G-quartet (G4) feature in its miRNA and mRNA targets. ‘Translational enhancer’ that drives specific mRNAs to polysomes and increases the efficiency of protein synthesis. Its association with the translational machinery and target mRNAs results in an increased number of initiation events per molecule of mRNA and, indirectly, in mRNA stabilization. Binds IGF2 mRNA, MYOD1 mRNA, ARBP/36B4 ribosomal protein mRNA and its own mRNA. Essential for skeletal muscle differentiation program through the translational up-regulation of IGF2 expression. Suppressor of microRNA (miRNA) biogenesis, including that of let-7, miR107, miR-143 and miR-200c. Specifically binds the miRNA precursors (pre-miRNAs), recognizing an 5’-GGAG-3’ motif found in pre-miRNA terminal loop, and recruits TUT4 and TUT7 uridylyltransferases. This results in the terminal uridylation of target pre-miRNAs. Uridylated pre-miRNAs fail to be processed by Dicer and undergo degradation. The repression of let-7 expression is required for normal development and contributes to maintain the pluripotent state by preventing let-7-mediated differentiation of embryonic stem cells. Localized to the periendoplasmic reticulum area, binds to a large number of spliced mRNAs and inhibits the translation of mRNAs destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Binds to and enhances the translation of mRNAs for several metabolic enzymes, such as PFKP, PDHA1 or SDHA, increasing glycolysis and oxidative phosphorylation. Which, with the let-7 repression may enhance tissue repair in adult tissue.

Subunit / interactions. Monomer. During skeletal muscle differentiation, associated with translation initiation complexes in the polysomal compartment. Directly interacts with EIF3S2. Interacts with NCL in an RNA-dependent manner. Interacts (via C-terminus) with DHX9 (via N- and C-terminus); this interaction occurs in a RNA-independent manner. Interacts with TUT4 in the presence of pre-let-7 RNA.

Subcellular location. Cytoplasm. Rough endoplasmic reticulum. P-body. Stress granule. Nucleus. Nucleolus.

Tissue specificity. Expressed in embryonic stem cells, placenta and testis. Tends to be up-regulated in HER2-overexpressing breast tumors.

Domain organisation. The CSD domain is required for function in muscle differentiation. The CCHC zinc fingers interact with the GGAG motif at the 3’ end of let-7 miRNAs precursors, more generally they bind the 5’-NGNNG-3’ consensus motif with micromolar affinity. The CSD domain recognizes the loop at the 5’ end. The flexible linker allows accommodating variable sequences and lengths among let-7 family members.

Induction. Can be negatively regulated by the interaction of microRNAs miR-125a and miR-125b with at least two miRNA responsive elements (miREs) in the 3’-UTR of this gene. These interactions may reduce both translation efficiency and mRNA abundance. Negatively regulated by retinoic acid.

Miscellaneous. Overexpressed in primary tumors (overall frequency approximately 15%), overexpression being linked to repression of let-7 family miRNAs and derepression of let-7 targets. Facilitates cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Reactivation of LIN28A expression enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics. Improves hair regrowth by promoting anagen in hair follicle and accelerates regrowth of cartilage, bone and mesenchyme after ear and digit injuries.

Similarity. Belongs to the lin-28 family.

RefSeq proteins (1): NP_078950* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001878	Znf_CCHC	Domain
IPR002059	CSP_DNA-bd	Domain
IPR011129	CSD	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR036875	Znf_CCHC_sf	Homologous_superfamily
IPR051373	Lin-28_RNA-binding	Family
IPR054081	Lin-28A-like_Znf-CCHC_2	Domain

Pfam: PF00098, PF00313, PF21890

UniProt features (34 total): strand 8, mutagenesis site 5, helix 5, modified residue 4, turn 4, region of interest 3, zinc finger region 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5UDZ	X-RAY DIFFRACTION	2
8OPT	ELECTRON MICROSCOPY	3.65
8OST	ELECTRON MICROSCOPY	3.69
9W4R	ELECTRON MICROSCOPY	3.78
8OPS	ELECTRON MICROSCOPY	3.82
9W4S	ELECTRON MICROSCOPY	3.82
2CQF	SOLUTION NMR
2LI8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9Z2-F1	76.53	0.43

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 (4): 120, 200, 2, 3

Mutagenesis-validated functional residues (5):

Position	Phenotype
46	does not affect localization to p-bodies; when associated with a-55 and a-73.
55	does not affect localization to p-bodies; when associated with a-46 and a-73.
73	does not affect localization to p-bodies; when associated with a-46 and a-55.
147	abolishes ability to suppress pre-let-7 biogenesis and localization to p-bodies without affecting pre-let-7 binding; whe
169	abolishes ability to suppress pre-let-7 biogenesis and localization to p-bodies without affecting pre-let-7 binding; whe

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 294 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GCACCTT_MIR18A_MIR18B, FXR_IR1_Q6, MYAATNNNNNNNGGC_UNKNOWN, ACTACCT_MIR196A_MIR196B, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, PAX4_01, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_NEGATIVE_REGULATION_OF_GLIOGENESIS, LFA1_Q6, TTTGTAG_MIR520D, SP3_Q3, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, MAZ_Q6, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS

GO Biological Process (20): germ cell development (GO:0007281), miRNA catabolic process (GO:0010587), negative regulation of translation (GO:0017148), stem cell population maintenance (GO:0019827), pre-miRNA processing (GO:0031054), RNA 3’-end processing (GO:0031123), positive regulation of TOR signaling (GO:0032008), positive regulation of neuron differentiation (GO:0045666), negative regulation of glial cell differentiation (GO:0045686), stem cell differentiation (GO:0048863), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to glucose stimulus (GO:0071333), positive regulation of cell proliferation involved in kidney development (GO:1901724), negative regulation of pre-miRNA processing (GO:2000632), positive regulation of cytoplasmic translation (GO:2000767), miRNA metabolic process (GO:0010586), post-transcriptional regulation of gene expression (GO:0010608), regulatory ncRNA-mediated gene silencing (GO:0031047), positive regulation of translation (GO:0045727), regulation of miRNA-mediated gene silencing (GO:0060964)

GO Molecular Function (12): G-quadruplex RNA binding (GO:0002151), RNA binding (GO:0003723), mRNA binding (GO:0003729), zinc ion binding (GO:0008270), translation initiation factor binding (GO:0031369), miRNA binding (GO:0035198), pre-miRNA binding (GO:0070883), protein-RNA adaptor activity (GO:0140517), sequence-specific mRNA binding (GO:1990825), nucleic acid binding (GO:0003676), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): P-body (GO:0000932), nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), rough endoplasmic reticulum (GO:0005791), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), endoplasmic reticulum (GO:0005783)

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 binding	3
translation	2
regulation of translation	2
negative regulation of gene expression	2
positive regulation of intracellular signal transduction	2
binding	2
cytoplasmic ribonucleoprotein granule	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
developmental process involved in reproduction	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
RNA catabolic process	1
miRNA metabolic process	1
negative regulation of protein metabolic process	1
multicellular organismal process	1
maintenance of cell number	1
miRNA processing	1
RNA processing	1
TOR signaling	1
regulation of TOR signaling	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
glial cell differentiation	1
negative regulation of gliogenesis	1
regulation of glial cell differentiation	1
cell differentiation	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
positive regulation of cell population proliferation	1
cell proliferation involved in kidney development	1
pre-miRNA processing	1
negative regulation of miRNA processing	1
regulation of pre-miRNA processing	1

Protein interactions and networks

STRING

3230 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LIN28A	TUT4	Q5TAX3	995
LIN28A	POU5F1	P31359	972
LIN28A	TUT7	Q5VYS8	966
LIN28A	SOX2	P48431	962
LIN28A	NANOG	Q9H9S0	947
LIN28A	KLF4	P78338	945
LIN28A	MYC	P01106	869
LIN28A	TUT1	Q9H6E5	865
LIN28A	PRDM14	Q9GZV8	830
LIN28A	HNRNPA1	P09651	804
LIN28A	FBXO15	Q8NCQ5	800
LIN28A	DROSHA	Q9NRR4	783
LIN28A	DHX9	Q08211	771
LIN28A	MYCL	P12524	763
LIN28A	DIS3L2	Q8IYB7	762

IntAct

52 interactions, top by confidence:

A	B	Type	Score
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
LIN28A	ZNF275	psi-mi:“MI:0915”(physical association)	0.560
LIN28A		psi-mi:“MI:0915”(physical association)	0.560
HTT	LIN28A	psi-mi:“MI:0915”(physical association)	0.560
LIN28A	EIF3D	psi-mi:“MI:0914”(association)	0.550
LIN28A	EIF3D	psi-mi:“MI:2364”(proximity)	0.550
LIN28A	EIF3D	psi-mi:“MI:0403”(colocalization)	0.550

BioGRID (477): LIN28A (Two-hybrid), LIN28A (Affinity Capture-Western), TRIM25 (Affinity Capture-Western), MIRLET7A1 (Protein-RNA), LIN28A (Affinity Capture-RNA), LIN28A (Affinity Capture-RNA), LIN28A (Affinity Capture-MS), LIN28A (Affinity Capture-MS), USP28 (Affinity Capture-Western), LIN28A (Affinity Capture-Western), LIN28A (Two-hybrid), FBXL19-AS1 (Affinity Capture-RNA), LIN28A (Protein-RNA), LIN28A (Protein-RNA), LIN28A (Protein-RNA)

ESM2 similar proteins: A0JN71, A4FV61, D3YYI7, O15034, O43189, O75995, O88842, P29590, P52734, P55266, P78314, P98174, Q14CM0, Q45KJ4, Q45KJ5, Q45KJ6, Q497H0, Q4R4I0, Q58D05, Q5E9N3, Q5EB47, Q5U2M7, Q5XI70, Q66J85, Q6P5G6, Q6P9L4, Q6ZN17, Q70CQ1, Q70EL4, Q803L0, Q8AVK2, Q8BUM9, Q8CE64, Q8JHC4, Q8K214, Q8K352, Q8K3Y3, Q8N554, Q8QFX1, Q8TC41

Diamond homologs: A0R5E1, B5DE31, E0J1Q3, E0J500, E1WGN1, O30875, O54310, O65639, P0A105, P0A106, P0A352, P0A353, P0A354, P0A362, P0A363, P0A968, P0A969, P0A970, P0A971, P0A972, P0A973, P0A974, P0A975, P0A978, P0A979, P0A980, P0A981, P0A986, P0A987, P0A9X9, P0A9Y0, P0A9Y1, P0A9Y2, P0A9Y3, P0A9Y4, P0A9Y5, P0A9Y6, P0A9Y7, P0A9Y8, P0A9Y9

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MAPK3	“down-regulates activity”	LIN28A	phosphorylation
MAPK1	“down-regulates activity”	LIN28A	phosphorylation
LIN28A	“up-regulates quantity by expression”	IGF2	“translation regulation”
SOX2/POU5F1	“up-regulates quantity by expression”	LIN28A	“transcriptional regulation”
SOX17/POU5F1	“up-regulates quantity by expression”	LIN28A	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

642 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26411381:TCCA:T	acceptor_loss	1.0000
1:26411382:CCAG:C	acceptor_loss	1.0000
1:26411384:A:AG	acceptor_gain	1.0000
1:26411384:AGGT:A	acceptor_gain	1.0000
1:26411385:G:GA	acceptor_gain	1.0000
1:26411385:GGT:G	acceptor_gain	1.0000
1:26411385:GGTG:G	acceptor_gain	1.0000
1:26411579:CCAGG:C	donor_loss	1.0000
1:26411580:CAG:C	donor_loss	1.0000
1:26411581:AGGTG:A	donor_loss	1.0000
1:26411582:GGTGA:G	donor_loss	1.0000
1:26411583:G:T	donor_loss	1.0000
1:26425298:A:AG	acceptor_gain	1.0000
1:26425301:A:AG	acceptor_gain	1.0000
1:26425302:G:GG	acceptor_gain	1.0000
1:26425302:GA:G	acceptor_gain	1.0000
1:26425302:GAGT:G	acceptor_gain	1.0000
1:26425302:GAGTA:G	acceptor_gain	1.0000
1:26425413:TG:T	donor_gain	1.0000
1:26425414:GG:G	donor_gain	1.0000
1:26425452:A:T	donor_gain	1.0000
1:26410918:TGCAG:T	donor_loss	0.9900
1:26410920:CAG:C	donor_loss	0.9900
1:26410921:AGG:A	donor_loss	0.9900
1:26410922:GGT:G	donor_loss	0.9900
1:26410923:GTTCG:G	donor_loss	0.9900
1:26410924:T:A	donor_loss	0.9900
1:26411384:AG:A	acceptor_gain	0.9900
1:26411384:AGGTG:A	acceptor_gain	0.9900
1:26411385:GG:G	acceptor_gain	0.9900

AlphaMissense

1375 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26411478:G:C	G42R	1.000
1:26411479:G:A	G42D	1.000
1:26411484:T:C	C44R	1.000
1:26411485:G:A	C44Y	1.000
1:26411485:G:T	C44F	1.000
1:26411486:T:G	C44W	1.000
1:26411487:A:G	K45E	1.000
1:26411489:G:C	K45N	1.000
1:26411489:G:T	K45N	1.000
1:26411490:T:A	W46R	1.000
1:26411490:T:C	W46R	1.000
1:26411491:G:C	W46S	1.000
1:26411491:G:T	W46L	1.000
1:26411492:G:C	W46C	1.000
1:26411492:G:T	W46C	1.000
1:26411493:T:A	F47I	1.000
1:26411493:T:C	F47L	1.000
1:26411493:T:G	F47V	1.000
1:26411494:T:C	F47S	1.000
1:26411494:T:G	F47C	1.000
1:26411495:C:A	F47L	1.000
1:26411495:C:G	F47L	1.000
1:26411498:C:A	N48K	1.000
1:26411498:C:G	N48K	1.000
1:26411508:G:A	G52R	1.000
1:26411508:G:C	G52R	1.000
1:26411508:G:T	G52W	1.000
1:26411509:G:A	G52E	1.000
1:26411509:G:T	G52V	1.000
1:26411511:T:A	F53I	1.000

dbSNP variants (sampled 300 via entrez): RS1000171638 (1:26419111 G>A), RS1000406104 (1:26411907 G>A,C,T), RS1000423129 (1:26411134 G>A,T), RS1000448239 (1:26422910 T>C), RS1000461672 (1:26418137 G>A), RS1000462024 (1:26411368 G>A), RS1000552327 (1:26422163 T>G), RS1000815693 (1:26416443 C>T), RS1001589384 (1:26410559 T>C), RS1001623892 (1:26410418 A>C,G,T), RS1001734569 (1:26410460 C>G), RS1001816144 (1:26414841 T>G), RS1001847098 (1:26415221 T>C), RS1001930093 (1:26421568 G>C,T), RS1002120421 (1:26421247 G>C)

Disease associations

OMIM: gene MIM:611043 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000817_137	Height	3.000000e-08
GCST002726_64	Glucose homeostasis traits	6.000000e-06
GCST011124_13	Caffeine consumption from tea	2.000000e-08
GCST90000025_909	Appendicular lean mass	2.000000e-28
GCST90002390_592	Mean corpuscular hemoglobin	1.000000e-16
GCST90002392_156	Mean corpuscular volume	3.000000e-26

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006830	insulin metabolic clearance rate measurement
EFO:0010091	tea consumption measurement
EFO:0004980	appendicular lean mass
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4523458 (SINGLE PROTEIN), CHEMBL4523614 (PROTEIN FAMILY)

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 7 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.60	IC50	2500	nM	CHEMBL1472575
5.39	IC50	4030	nM	CHEMBL4556019
5.32	IC50	4800	nM	CHEMBL4439278
5.23	Kd	5900	nM	CHEMBL4439278
5.16	IC50	7000	nM	CHEMBL1314668
5.10	IC50	8000	nM	CHEMBL1733963

PubChem BioAssay actives

6 with measured affinity, of 56 total; 5 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
N,N,N’,N’-tetrakis(pyridin-2-ylmethyl)ethane-1,2-diamine	1930527: Inhibition of LIN28A (unknown origin) by FRET assay	ic50	2.5000	uM
4-[4,4-dimethyl-8-nitro-7-(4-phenylmethoxycarbonylpiperazin-1-yl)chromeno[3,4-d]pyrazol-1-yl]benzoic acid	1930527: Inhibition of LIN28A (unknown origin) by FRET assay	ic50	4.0300	uM
5,8-dichloro-2-(2,4-dichloroanilino)-4-oxo-1H-quinoline-3-carboxamide	1533042: Inhibition of Cy5-preE-let-7g binding to recombinant human N-terminal His6-tagged Lin28a expressed in Escherichia coli Rosetta2 (DE3) pLysS measured after 30 to 60 mins by electrophoretic mobility shift assay	ic50	4.8000	uM
4-[(3aS,4R,9bR)-6-ethoxy-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl]benzoic acid	1930527: Inhibition of LIN28A (unknown origin) by FRET assay	ic50	7.0000	uM
N-methyl-N-[3-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide	1930527: Inhibition of LIN28A (unknown origin) by FRET assay	ic50	8.0000	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases expression	4
methylmercuric chloride	decreases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Carbamazepine	affects expression, decreases expression	2
Valproic Acid	decreases expression	2
FR900359	decreases phosphorylation	1
napabucasin	decreases expression	1
sodium arsenite	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
LDN 193189	decreases expression, affects cotreatment	1
Decitabine	increases expression	1
Lamotrigine	decreases expression	1
Arsenic	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Deoxyglucose	decreases reaction, increases expression, decreases expression	1
Oxygen	decreases reaction, increases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
T-2 Toxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Cadmium Chloride	increases expression	1
Palmitic Acid	increases expression	1

ChEMBL screening assays

45 unique, capped per target: 45 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4329767	Binding	Inhibition of Cy5-preE-let-7g binding to recombinant human N-terminal His6-tagged Lin28a expressed in Escherichia coli Rosetta2 (DE3) pLysS measured after 30 to 60 mins by electrophoretic mobility shift assay	Restoring Let-7 microRNA Biogenesis Using a Small-Molecule Inhibitor of the Protein-RNA Interaction. — ACS Med Chem Lett

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3X4	SEES3-1V human LIN28, clone1	Embryonic stem cell	Male
CVCL_A3X5	SEES3-1V human LIN28, clone2	Embryonic stem cell	Male
CVCL_A3X6	SEES3-1V human LIN28, clone3	Embryonic stem cell	Male
CVCL_B8JS	Abcam HCT 116 LIN28A KO	Cancer cell line	Male
CVCL_B9M1	Abcam A-549 LIN28A KO	Cancer cell line	Male
CVCL_D2G8	Abcam MCF-7 LIN28A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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