BROX

gene
On this page

Also known as FLJ32421

Summary

BROX (BRO1 domain and CAAX motif containing, HGNC:26512) is a protein-coding gene on chromosome 1q41, encoding BRO1 domain-containing protein BROX (Q5VW32). Nuclear envelope-associated factor that is involved in the nuclear envelope ruptures during interphase (NERDI) repair, where it is locally recruited by CHMP5 and reduces cytoskeletal stress through its action on SYN2 to help reseal the ruptured membrane.

Involved in mitotic nuclear membrane reassembly. Located in nuclear envelope.

Source: NCBI Gene 148362 — RefSeq curated summary.

At a glance

  • Clinical variants (ClinVar): 56 total
  • Druggable target: yes
  • MANE Select transcript: NM_144695

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:26512
Approved symbolBROX
NameBRO1 domain and CAAX motif containing
Location1q41
Locus typegene with protein product
StatusApproved
AliasesFLJ32421
Ensembl geneENSG00000162819
Ensembl biotypeprotein_coding
Entrez148362

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 21 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000340934, ENST00000426638, ENST00000469236, ENST00000473962, ENST00000489191, ENST00000496267, ENST00000537020, ENST00000539697, ENST00000612948, ENST00000888412, ENST00000888413, ENST00000916810, ENST00000916814, ENST00000916816, ENST00000916817, ENST00000916818, ENST00000962607, ENST00000962608, ENST00000962609, ENST00000962610, ENST00000962611, ENST00000962612, ENST00000962613, ENST00000962614, ENST00000962615

RefSeq mRNA: 6 — MANE Select: NM_144695 NM_001288579, NM_001288580, NM_001288581, NM_001375661, NM_001375758, NM_144695

CCDS: CCDS1534, CCDS73036, CCDS73037

Canonical transcript exons

ENST00000340934 — 13 exons

ExonStartEnd
ENSE00001068953222722419222722514
ENSE00001068955222728743222728828
ENSE00001068957222729620222729701
ENSE00001068958222727168222727257
ENSE00001068962222731357222731516
ENSE00001068963222730027222730177
ENSE00003598268222725450222725555
ENSE00003600801222718925222719031
ENSE00003612560222724092222724164
ENSE00003628196222715684222715800
ENSE00003674541222719263222719359
ENSE00003841794222732628222735187
ENSE00003845726222712564222712942

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 98.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.7380 / max 215.3625, expressed in 1818 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter IDTPM avgSamples expressed
872410.09301762
87268.20181716
87287.73531704
87273.41701206
87253.17361431
87290.117249

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
ileal mucosaUBERON:000033198.46gold quality
cardiac muscle of right atriumUBERON:000337997.79gold quality
palpebral conjunctivaUBERON:000181297.73gold quality
nasal cavity epitheliumUBERON:000538497.32gold quality
upper arm skinUBERON:000426397.24gold quality
corpus callosumUBERON:000233697.16gold quality
calcaneal tendonUBERON:000370196.89gold quality
jejunal mucosaUBERON:000039996.82gold quality
ponsUBERON:000098896.80gold quality
trigeminal ganglionUBERON:000167596.69gold quality
mucosa of sigmoid colonUBERON:000499396.65gold quality
corpus epididymisUBERON:000435996.56gold quality
left ventricle myocardiumUBERON:000656696.53gold quality
kidney epitheliumUBERON:000481996.45gold quality
mucosa of paranasal sinusUBERON:000503096.40gold quality
esophagus squamous epitheliumUBERON:000692096.40gold quality
colonic mucosaUBERON:000031796.21gold quality
tibialis anteriorUBERON:000138596.09gold quality
deltoidUBERON:000147696.06gold quality
oral cavityUBERON:000016796.03gold quality
epithelium of nasopharynxUBERON:000195195.94gold quality
penisUBERON:000098995.93gold quality
bronchial epithelial cellCL:000232895.84gold quality
subthalamic nucleusUBERON:000190695.83gold quality
bronchusUBERON:000218595.71gold quality
caput epididymisUBERON:000435895.61gold quality
pharyngeal mucosaUBERON:000035595.55gold quality
lateral globus pallidusUBERON:000247695.54gold quality
inferior vagus X ganglionUBERON:000536395.50gold quality
medulla oblongataUBERON:000189695.46gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-MTAB-6058no1549.53
E-MTAB-4850no412.24
E-ANND-3no0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-5011-5P100.0083.465820
HSA-MIR-3613-3P100.0076.367965
HSA-MIR-190A-3P100.0080.355520
HSA-MIR-4476100.0068.182030
HSA-MIR-6876-5P100.0067.682126
HSA-MIR-4533100.0069.482758
HSA-MIR-3163100.0077.238605
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-453199.9969.703181
HSA-MIR-428299.9975.366408
HSA-MIR-4789-5P99.9870.762721
HSA-MIR-1213699.9872.815713
HSA-MIR-3065-5P99.9771.563281
HSA-MIR-60799.9773.625593
HSA-MIR-568899.9673.234504
HSA-MIR-495-3P99.9672.814197
HSA-MIR-548AJ-3P99.9673.385345
HSA-MIR-548X-3P99.9673.385345
HSA-MIR-1250-3P99.9670.044038
HSA-MIR-570-3P99.9672.414910
HSA-MIR-365899.9673.874379
HSA-MIR-548AB99.9571.313488
HSA-MIR-55999.9572.283609
HSA-MIR-548J-3P99.9472.614881
HSA-MIR-548A-5P99.9471.273482
HSA-MIR-548AD-5P99.9471.233502
HSA-MIR-548AE-5P99.9471.233502
HSA-MIR-548AK99.9471.243488
HSA-MIR-548AM-5P99.9471.243488
HSA-MIR-548AP-5P99.9471.143489

Literature-anchored findings (GeneRIF, showing 4)

  • Results revealed that Strep-Brox(WT) exhibited accumulation in the perinuclear area suggested physiological significance of farnesylation of Brox in its subcellular distribution and efficient interaction with CHMP4s in vivo. (PMID:18190528)
  • structural analysis of the Bro1 domain protein BROX and functional analyses of the ALIX Bro1 domain in HIV-1 budding (PMID:22162750)
  • homologous domain of human Bro1 domain-containing proteins, Alix and Brox, binds CHMP4B but not STAM2, despite their high structural similarity (PMID:26866605)
  • BROX haploinsufficiency in familial nonmedullary thyroid cancer. (PMID:32385852)

Cross-species orthologs

4 orthologs

OrganismSymbolGene ID
danio_reriobroxENSDARG00000013659
mus_musculusBroxENSMUSG00000046836
rattus_norvegicusBroxENSRNOG00000052963
caenorhabditis_elegansWBGENE00015219

Protein

Protein identifiers

BRO1 domain-containing protein BROXQ5VW32 (reviewed: Q5VW32)

Alternative names: BRO1 domain- and CAAX motif-containing protein

All UniProt accessions (3): Q5VW32, F5GXQ0, Q5VW33

UniProt curated annotations — full annotation on UniProt →

Function. Nuclear envelope-associated factor that is involved in the nuclear envelope ruptures during interphase (NERDI) repair, where it is locally recruited by CHMP5 and reduces cytoskeletal stress through its action on SYN2 to help reseal the ruptured membrane.

Subunit / interactions. Monomer. Interacts with CHMP4B. Interacts with CHMP5: this interaction allows the recruitment of BROX to cellular membranes. Interacts with SYN2; this interaction promotes SYN2 ubiquitination and facilitates the relaxation of mechanical stress imposed by compressive actin fibers at the rupture site.

Subcellular location. Nucleus membrane.

Post-translational modifications. Farnesylation is required for nuclear envelope localization.

Similarity. Belongs to the BROX family.

Isoforms (2)

UniProt IDNamesCanonical?
Q5VW32-11yes
Q5VW32-22

RefSeq proteins (6): NP_001275508, NP_001275509, NP_001275510, NP_001362590, NP_001362687, NP_653296* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR004328BRO1_domDomain
IPR038499BRO1_sfHomologous_superfamily
IPR038898BROXFamily

Pfam: PF03097

UniProt features (36 total): helix 15, strand 7, mutagenesis site 3, modified residue 2, chain 1, propeptide 1, sequence conflict 1, turn 1, domain 1, region of interest 1, compositionally biased region 1, lipid moiety-binding region 1, splice variant 1

Structure

Experimental structures (PDB)

7 structures.

PDBMethodResolution (Å)
3R9MX-RAY DIFFRACTION1.95
3ZXPX-RAY DIFFRACTION2.5
3UM2X-RAY DIFFRACTION2.59
3ULYX-RAY DIFFRACTION2.6
3UM1X-RAY DIFFRACTION2.71
3UM0X-RAY DIFFRACTION3.1
3UM3X-RAY DIFFRACTION3.8

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q5VW32-F192.150.84

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 (3): 283, 408, 408

Mutagenesis-validated functional residues (3):

PositionPhenotype
350loss of syn2 interaction. abolishes brox recruitment to sites of nuclear envelope (ne) rupture. impairs ne resealing. do
408loss of association with the nuclear envelop. abolishes its recruitment to rupture sites. abolishes its repair function.
204does not affect syn2 interaction. does not induce syn2 ubiquitination. does not affect recruitment to sites of rupture.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, MAYBURD_RESPONSE_TO_L663536_UP, GOBP_ORGANELLE_FISSION, GOBP_NUCLEUS_ORGANIZATION, GOBP_MITOTIC_NUCLEAR_DIVISION, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_MITOTIC_CELL_CYCLE, GOBP_NUCLEAR_ENVELOPE_ORGANIZATION, GOBP_MEMBRANE_ORGANIZATION, OSMAN_BLADDER_CANCER_DN, GOCC_NUCLEAR_ENVELOPE, GOCC_NUCLEAR_MEMBRANE, GOBP_CELL_CYCLE_PROCESS, GOCC_ORGANELLE_ENVELOPE

GO Biological Process (1): mitotic nuclear membrane reassembly (GO:0007084)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): nuclear envelope (GO:0005635), nuclear membrane (GO:0031965), extracellular exosome (GO:0070062), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
nucleus2
mitotic cell cycle1
nuclear membrane reassembly1
mitotic nuclear membrane organization1
binding1
endomembrane system1
organelle envelope1
nuclear envelope1
organelle membrane1
extracellular vesicle1
intracellular membrane-bounded organelle1
cellular anatomical structure1

Protein interactions and networks

STRING

843 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
BROXCHMP6Q96FZ7590
BROXCHMP4AQ9BY43540
BROXCHMP5Q9NZZ3512
BROXVPS28Q9UK41507
BROXSTAM2O75886494
BROXVPS25Q9BRG1480
BROXCHMP3Q9Y3E7466
BROXA0A140T963A0A140T963466
BROXVTA1Q9NP79462
BROXRHBDD2Q6NTF9459
BROXANO7Q6IWH7459
BROXSNF8Q96H20459
BROXTSG101Q99816458
BROXHABP2Q14520450
BROXCHMP1AQ9HD42446

IntAct

63 interactions, top by confidence:

ABTypeScore
BROXCHMP5psi-mi:“MI:0407”(direct interaction)0.610
BROXCHMP5psi-mi:“MI:0915”(physical association)0.610
BROXCHMP4Bpsi-mi:“MI:0407”(direct interaction)0.610
BROXCHMP4Bpsi-mi:“MI:0915”(physical association)0.610
BROXTCEA1psi-mi:“MI:0914”(association)0.560
BROXTCEA1psi-mi:“MI:0915”(physical association)0.560
BROXCHMP4Apsi-mi:“MI:0915”(physical association)0.400
BROXCHMP4Cpsi-mi:“MI:0915”(physical association)0.400
BROXHNRNPCL2psi-mi:“MI:0915”(physical association)0.400
TK2psi-mi:“MI:0915”(physical association)0.400
BROXpsi-mi:“MI:0915”(physical association)0.370
NS3C15orf61psi-mi:“MI:0914”(association)0.350
SHTN1psi-mi:“MI:0914”(association)0.350
TNFRSF10Apsi-mi:“MI:0914”(association)0.350
RNF149CCDC85Cpsi-mi:“MI:0914”(association)0.350
NFYANME2P1psi-mi:“MI:0914”(association)0.350
ZDHHC6A2ML1psi-mi:“MI:0914”(association)0.350
AIMP1IGF2BP3psi-mi:“MI:0914”(association)0.350
AIMP1TRAFD1psi-mi:“MI:0914”(association)0.350
MAVSCHMP2Apsi-mi:“MI:0914”(association)0.350
CACYBPVPS37Cpsi-mi:“MI:0914”(association)0.350
CACYBPPSMD11psi-mi:“MI:0914”(association)0.350

BioGRID (52): BROX (Co-fractionation), LDHA (Co-fractionation), PDCD6IP (Co-fractionation), SORD (Co-fractionation), TCEA1 (Affinity Capture-MS), CHMP1A (Affinity Capture-MS), IPO9 (Affinity Capture-MS), BROX (Affinity Capture-MS), BROX (Affinity Capture-MS), BROX (Affinity Capture-MS), BROX (Proximity Label-MS), BROX (Affinity Capture-MS), BROX (Affinity Capture-MS), BROX (Affinity Capture-MS), TCEA1 (Affinity Capture-MS)

ESM2 similar proteins: A3KQV2, A4IIL4, O00471, O54921, P48553, P62944, P63009, P63010, P79020, P97878, Q00004, Q0IIZ5, Q1L8F9, Q29RF7, Q3SYS9, Q3TLI0, Q3TPX4, Q498H0, Q4G074, Q4QR29, Q4V8K5, Q4VA53, Q5F3K0, Q5KU05, Q5R6J0, Q5RDD7, Q5VW32, Q5VYK3, Q62018, Q6DDM4, Q6DEU9, Q6IR80, Q6P1I3, Q6PD62, Q6PDI5, Q6TRW4, Q6ZPU9, Q8BMA6, Q8K2Q7, Q8WUM4

Diamond homologs: A3KQV2, A4IIL4, Q22885, Q4V8K5, Q5RDD7, Q5VW32, Q8K2Q7, Q756C5, Q12033, Q6CU63, Q8WZL4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 59 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:

PathwayPartnersFoldFDR
Budding and maturation of HIV virion661.2×1e-07
Endosomal Sorting Complex Required For Transport (ESCRT)655.3×1e-07
Sealing of the nuclear envelope (NE) by ESCRT-III543.3×6e-06
Late endosomal microautophagy540.8×6e-06
HCMV Late Events512.3×2e-03

GO biological processes:

GO termPartnersFoldFDR
nuclear membrane reassembly6110.1×4e-09
late endosome to lysosome transport591.8×7e-08
viral budding via host ESCRT complex689.2×6e-09
multivesicular body sorting pathway574.3×2e-07
midbody abscission567.8×3e-07
regulation of mitotic spindle assembly567.8×3e-07
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway660.4×3e-08
multivesicular body assembly658.5×3e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance39
Likely benign1
Benign2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1980 predictions. Top by Δscore:

VariantEffectΔscore
1:222713668:G:GGdonor_gain1.0000
1:222713703:GGAA:Gdonor_gain1.0000
1:222713704:G:GTdonor_gain1.0000
1:222713726:G:GTdonor_gain1.0000
1:222713726:GAA:Gdonor_gain1.0000
1:222713760:C:Gdonor_gain1.0000
1:222715682:A:AGacceptor_gain1.0000
1:222715683:G:GGacceptor_gain1.0000
1:222715797:GCAA:Gdonor_gain1.0000
1:222715799:AAGT:Adonor_loss1.0000
1:222715800:AG:Adonor_loss1.0000
1:222715801:G:GGdonor_gain1.0000
1:222715801:GTA:Gdonor_loss1.0000
1:222715802:T:Adonor_loss1.0000
1:222718921:T:Gacceptor_gain1.0000
1:222718922:A:AGacceptor_gain1.0000
1:222718922:AAGT:Aacceptor_gain1.0000
1:222718923:A:AGacceptor_gain1.0000
1:222718924:G:GGacceptor_gain1.0000
1:222718924:GT:Gacceptor_gain1.0000
1:222719258:TATA:Tacceptor_loss1.0000
1:222719260:TA:Tacceptor_loss1.0000
1:222719261:A:ACacceptor_loss1.0000
1:222719261:A:AGacceptor_gain1.0000
1:222719262:G:GAacceptor_gain1.0000
1:222719353:TTCCA:Tdonor_gain1.0000
1:222719356:CAAGG:Cdonor_loss1.0000
1:222719357:AAGG:Adonor_loss1.0000
1:222719358:AGGTA:Adonor_loss1.0000
1:222719359:GGTAA:Gdonor_loss1.0000

AlphaMissense

2678 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
1:222719328:T:AW92R1.000
1:222719328:T:CW92R1.000
1:222728784:T:AW238R1.000
1:222728784:T:CW238R1.000
1:222715709:T:AW4R0.999
1:222715709:T:CW4R0.999
1:222715719:G:TR7M0.999
1:222715732:A:CK11N0.999
1:222715732:A:TK11N0.999
1:222724130:T:CL147P0.999
1:222724139:C:AA150E0.999
1:222724141:G:CA151P0.999
1:222725540:G:CA189P0.999
1:222725541:C:AA189D0.999
1:222725546:G:CA191P0.999
1:222725547:C:AA191D0.999
1:222727180:G:CR198P0.999
1:222727182:G:CA199P0.999
1:222727183:C:AA199E0.999
1:222727216:C:AA210D0.999
1:222727224:G:CA213P0.999
1:222729636:G:AG258D0.999
1:222729671:G:CA270P0.999
1:222729684:T:CL274P0.999
1:222729692:G:CA277P0.999
1:222730169:T:AN327K0.999
1:222730169:T:GN327K0.999
1:222730177:T:AI330N0.999
1:222730177:T:CI330T0.999
1:222731358:T:GY331D0.999

dbSNP variants (sampled 300 via entrez): RS1000095755 (1:222711862 G>A), RS1000323571 (1:222715151 A>C), RS1000553936 (1:222728168 C>T), RS1000718400 (1:222715536 C>T), RS1000882652 (1:222735329 A>G), RS1000915108 (1:222715869 A>G,T), RS1001127741 (1:222731605 A>G), RS1001139450 (1:222727768 A>G,T), RS1001388798 (1:222718374 G>A,T), RS1001450338 (1:222725045 G>A,C), RS1001524508 (1:222712830 C>T), RS1001587791 (1:222718574 T>A), RS1001710497 (1:222734148 T>C), RS1001732869 (1:222715958 C>A,T), RS1001763014 (1:222733725 G>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066473 (SINGLE PROTEIN)

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

PharmGKB variants

2 variants.

VariantGenesLevelScore#Clin annotsDrugs
rs3748631AIDA, BROX0.000
rs35762933AIDA, BROX0.000

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
7.31Kd48.97nMCHEMBL5653589
7.31ED5048.97nMCHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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.

CompoundAssayTypeValueUnit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2147959: Binding affinity to human BROX incubated for 45 mins by Kinobead based pull down assaykd0.0490uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
Tobacco Smoke Pollutionaffects expression, increases expression2
GSK-J4increases expression1
bisphenol Faffects cotreatment, increases expression1
triphenyl phosphateaffects expression1
alpha-pineneincreases oxidation, increases abundance, affects cotreatment1
bisphenol Aaffects cotreatment, increases expression1
tris(1,3-dichloro-2-propyl)phosphateincreases expression1
sodium arseniteincreases expression1
tetrabromobisphenol Adecreases expression1
resorcinoldecreases expression1
methacrylaldehydeaffects cotreatment, increases oxidation, increases abundance1
2,2’,4,4’-tetrabromodiphenyl etherdecreases expression1
hexabrominated diphenyl ether 153decreases expression1
bisphenol Saffects cotreatment, increases expression1
jinfukangdecreases expression1
Acroleinaffects cotreatment, increases oxidation, increases abundance1
Air Pollutantsaffects cotreatment, increases abundance, increases oxidation1
Benzo(a)pyreneaffects methylation1
Dexamethasoneaffects cotreatment, increases expression1
Doxorubicindecreases expression1
Ethyl Methanesulfonateincreases expression1
Formaldehydeincreases expression1
Indomethacinaffects cotreatment, increases expression1
Ivermectindecreases expression1
Methyl Methanesulfonateincreases expression1
Ozoneaffects cotreatment, increases oxidation, increases abundance1
Phthalic Acidsincreases methylation1
Tretinoinincreases expression1
Urethaneincreases expression1
Valproic Acidincreases expression1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5651001BindingBinding affinity to human BROX incubated for 45 mins by Kinobead based pull down assayNVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.