# Histone and non-histone (de)acetylation impact on the blood-brain barrier **Authors:** Mariana Melo, Ana Fortuna, João Laranjinha, Joana Bicker PMC · DOI: 10.1186/s12987-026-00763-z · 2026-01-21 ## TL;DR This paper explores how histone and non-histone acetylation affects the blood-brain barrier's function and integrity. ## Contribution The paper highlights the role of HATs and HDACs in modulating the blood-brain barrier through epigenetic mechanisms. ## Key findings - HATs and HDACs influence BBB integrity by altering gene transcription in brain endothelial cells and related cell types. - The effects of HAT/HDAC activity on the BBB are context-dependent and vary across different pathologies. - Further studies in physiologically relevant models are needed to understand BBB modulation mechanisms. ## Abstract The blood-brain barrier (BBB) ensures the homeostasis of the central nervous system by regulating the composition of the brain interstitial fluid, required for proper brain function. Nonetheless, its properties are dynamic and susceptible to the influence of environmental factors acting through epigenetic mechanisms, among which are post-translational histone modifications. The activity of histone acetylases (HATs) and histone deacetylases (HDACs) on histone and non-histone substrates can alter gene transcription in brain endothelial cells, pericytes, astrocytes and microglia, leading to protective or detrimental effects on BBB integrity and function. These effects may range from the stabilization of intercellular junction proteins in brain endothelial cells to the modulation of neuroinflammation, with consequences on cognitive processes of memory and learning. Ultimately, the positive or negative outcome of HAT/HDAC activity is often context-dependent and varies across different pathologies, according to which corepressors or coactivators are recruited in intracellular signaling cascades, and their subsequent influence on gene expression. HATs/HDACs modulate the structural integrity and function of the BBB. Further studies in physiologically relevant BBB models are required, in order to provide greater mechanistic insight and overcome translational difficulties. ## Full-text entities - **Genes:** Sirt6 (sirtuin 6) [NCBI Gene 50721] {aka 2810449N18Rik, Sir2l6, mSIRT6}, Krit1 (KRIT1, ankyrin repeat containing) [NCBI Gene 79264] {aka 2010007K12Rik, A630036P20Rik, Ccm1}, ANGPT1 (angiopoietin 1) [NCBI Gene 284] {aka AGP1, AGPT, AGPT-1, ANG1, HAE5}, Rcor1 (REST corepressor 1) [NCBI Gene 217864] {aka 5730409O11, 6720480E22Rik, D12Wsu95e, Rocr1, mKIAA0071}, Mitf (melanogenesis associated transcription factor) [NCBI Gene 17342] {aka BCC2, Bhlhe32, Gsfbcc2, Vitiligo, Wh, bw}, HDAC4 (histone deacetylase 4) [NCBI Gene 9759] {aka AHO3, BDMR, HA6116, HD4, HDAC-4, HDAC-A}, Hdac3 (histone deacetylase 3) [NCBI Gene 15183], CREB1 (cAMP responsive element binding protein 1) [NCBI Gene 1385] {aka CREB, CREB-1}, HDAC8 (histone deacetylase 8) [NCBI Gene 55869] {aka CDA07, CDLS5, HD8, HDACL1, KDAC8, MRXS6}, Nus1 (NUS1 dehydrodolichyl diphosphate synthase subunit) [NCBI Gene 52014] {aka 1600027K07Rik, D10Ertd438e}, Brd4 (bromodomain containing 4) [NCBI Gene 57261] {aka Brd5, HUNK1, MCAP, WI-11513}, DNMT1 (DNA methyltransferase 1) [NCBI Gene 1786] {aka ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT}, Slc25a5 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5) [NCBI Gene 11740] {aka Ant2}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, SNCA (synuclein alpha) [NCBI Gene 6622] {aka NACP, PARK1, PARK4, PD1}, Gnai1 (G protein subunit alpha i1) [NCBI Gene 14677] {aka Gialpha1, Gnai-1, Hg1b}, PROCR (protein C receptor) [NCBI Gene 10544] {aka CCCA, CCD41, EPCR}, Myd88 (myeloid differentiation primary response gene 88) [NCBI Gene 17874], Hdac2 (histone deacetylase 2) [NCBI Gene 15182] {aka D10Wsu179e, YAF1, Yy1bp, mRPD3}, KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, Hdac3 (histone deacetylase 3) [NCBI Gene 84578], Cdh5 (cadherin 5) [NCBI Gene 12562] {aka 7B4, Cd144, VE-Cad, VECD, VEcad, Vec}, Orc1 (origin recognition complex, subunit 1) [NCBI Gene 18392] {aka MmORC1, Orc1l}, Hdac5 (histone deacetylase 5) [NCBI Gene 15184] {aka HD5, Hdac4, mHDA1, mKIAA0600}, ABCG2 (ATP binding cassette subfamily G member 2 (JR blood group)) [NCBI Gene 9429] {aka ABC15, ABCP, BCRP, BMDP, CD338, CDw338}, CYP4F3 (cytochrome P450 family 4 subfamily F member 3) [NCBI Gene 4051] {aka CPF3, CYP4F, CYPIVF3, LTB4H}, Acss2 (acyl-CoA synthetase short-chain family member 2) [NCBI Gene 60525] {aka 1110017C11Rik, ACAS, ACS, Acas1, Acas2, AceCS1}, Ocln (occludin) [NCBI Gene 18260] {aka Ocl}, Tmsb4x (thymosin, beta 4, X chromosome) [NCBI Gene 19241] {aka Ptmb4, Tb4, Tbeta4}, HMGB1 (high mobility group box 1) [NCBI Gene 3146] {aka HMG-1, HMG1, HMG3, SBP-1}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, Bdnf (brain derived neurotrophic factor) [NCBI Gene 12064], TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, Hmox1 (heme oxygenase 1) [NCBI Gene 15368] {aka D8Wsu38e, HO-1, HO1, Hemox, Hmox, Hsp32}, PPIG (peptidylprolyl isomerase G) [NCBI Gene 9360] {aka CARS-Cyp, CYP, SCAF10, SRCyp}, CREBBP (CREB binding lysine acetyltransferase) [NCBI Gene 1387] {aka CBP, KAT3A, MKHK1, RSTS, RSTS1}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, Bax (BCL2-associated X protein) [NCBI Gene 12028], Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, HDAC7 (histone deacetylase 7) [NCBI Gene 51564] {aka HD7, HD7A, HDAC7A}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, BRD4 (bromodomain containing 4) [NCBI Gene 23476] {aka CAP, CDLS6, FSHRG4, HUNK1, HUNKI, MCAP}, Nos2 (nitric oxide synthase 2, inducible) [NCBI Gene 18126] {aka MAC-NOS, NOS-II, Nos-2, Nos2a, i-NOS, iNOS}, Ppargc1a (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha) [NCBI Gene 19017] {aka A830037N07Rik, Gm11133, PGC-1, PPARGC-1-alpha, Pgc-1alpha, Pgc1}, Cldn5 (claudin 5) [NCBI Gene 12741] {aka MBEC1, Tmvcf}, Macroh2a1 (macroH2A.1 histone) [NCBI Gene 26914] {aka H2AF12M, H2afy, mH2a1}, GNAI1 (G protein subunit alpha i1) [NCBI Gene 2770] {aka Gi, HG1B, NEDHISB}, HDAC1 (histone deacetylase 1) [NCBI Gene 3065] {aka GON-10, HD1, KDAC1, RPD3, RPD3L1}, Gdnf (glial cell line derived neurotrophic factor) [NCBI Gene 14573] {aka ATF}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 17709], AHR (aryl hydrocarbon receptor) [NCBI Gene 196] {aka FVH3, RP85, bHLHe76}, Crebbp (CREB binding lysine acetyltransferase) [NCBI Gene 54244] {aka CBP, RSTS, RTS}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, ANGPT2 (angiopoietin 2) [NCBI Gene 285] {aka AGPT2, ANG2, LMPHM10}, Gfap (glial fibrillary acidic protein) [NCBI Gene 14580], Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56717] {aka 2610315D21Rik, FRAP, FRAP2, Frap1, RAFT1, RAPT1}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1} - **Diseases:** cutaneous T-cell lymphoma (MESH:D016410), autoimmune diseases (MESH:D001327), cerebral ischemia (MESH:D002545), mitochondrial dysfunction (MESH:D028361), infection (MESH:D007239), stroke (MESH:D020521), traumatic brain injury (MESH:D000070642), neuroinflammation (MESH:D000090862), multiple myeloma (MESH:D009101), demyelination (MESH:D003711), peripheral T cell lymphoma (MESH:D016411), migraine (MESH:D008881), ischemic stroke (MESH:D002544), neurodegeneration (MESH:D019636), glioblastoma (MESH:D005909), neuromuscular disorder (MESH:D009468), neurotoxic (MESH:D020258), CCM (MESH:D020786), neuronal (MESH:D009410), cancer (MESH:D009369), cytotoxic (MESH:D064420), hemorrhage (MESH:D006470), neurodevelopmental disorders (MESH:D002658), epilepsy (MESH:D004827), Experimental autoimmune encephalomyelitis (MESH:D004681), amyloid (MESH:C000718787), spinal cord injury (MESH:D013119), Depression (MESH:D003866), spinal cord (MESH:D013118), Alzheimer's disease (MESH:D000544), Neurological deficits (MESH:D009461), cognitive decline (MESH:D003072), Ischemia (MESH:D007511), bipolar disorder (MESH:D001714), injury (MESH:D014947), cerebral edema (MESH:D001929), R (MESH:C580424), brain injury (MESH:D001930), multiple sclerosis (MESH:D009103), OGD (MESH:C536050), astrocytoma (MESH:D001254), Huntington's (MESH:D006816), brain (MESH:D001927), I/R injury (MESH:D015427), Duchenne muscular dystrophy (MESH:D020388), Parkinson's disease (MESH:D010300), BBB dysfunction (MESH:C536830), anxiety (MESH:D001007), astrogliosis (MESH:D005911), CNS diseases (MESH:D002493), inflammation (MESH:D007249) - **Chemicals:** hydroxamic acids (MESH:D006877), panobinostat (MESH:D000077767), Valproic acid (MESH:D014635), Entinostat (MESH:C118739), amides (MESH:D000577), amino acid (MESH:D000596), memantine (MESH:D008559), vorinostat (MESH:D000077337), glucose (MESH:D005947), adenosine (MESH:D000241), vafidemstat (MESH:C000710213), Sodium butyrate (MESH:D020148), TSA (MESH:C481298), RGFP966 (MESH:C000603861), melatonin (MESH:D008550), rosiglitazone (MESH:D000077154), nitric oxide (MESH:D009569), 5hmC (-), exifone (MESH:C052932), Zinc (MESH:D015032), quisinostat (MESH:C541788), rutin (MESH:D012431), Lithium (MESH:D008094), short-chain fatty acids (MESH:D005232), 5-carboxylcytosine (MESH:C560974), 5fC (MESH:D005437), romidepsin (MESH:C087123), Dimethyl fumarate (MESH:D000069462), fenofibrate (MESH:D011345), 5-hydroxymethylcytosine (MESH:C011865), amines (MESH:D000588), FITC (MESH:D016650), Cyclic adenosine monophosphate (MESH:D000242), reactive oxygen species (MESH:D017382), L-arginine (MESH:D001120), belinostat (MESH:C487081), Lysines (MESH:D008239), Oxygen (MESH:D010100), sodium phenylbutyrate (MESH:C075773), benzamides (MESH:D001549), givinostat (MESH:C575255), Trichostatin A (MESH:C012589), GABA (MESH:D005680), 5-methylcytosine (MESH:D044503), NAD (MESH:D009243), flavonoid (MESH:D005419), manganese (MESH:D008345), 5-formylcytosine (MESH:C560973), Fluoxetine (MESH:D005473), LPS (MESH:D008070), retinoic acid (MESH:D014212), alcohol (MESH:D000438) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Mutations:** C5 position of cytosine - **Cell lines:** H4K5 — Mus musculus (Mouse), Hybridoma (CVCL_C5D1), PS19 — Mus musculus (Mouse), Hybridoma (CVCL_9225), N2A — Mus musculus (Mouse), Mouse neuroblastoma, Cancer cell line (CVCL_0470), BEC — Mus musculus (Mouse), Hybridoma (CVCL_RQ14), cells — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_M624), hCMEC — Homo sapiens (Human), Transformed cell line (CVCL_U985) ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12829097/full.md --- Source: https://tomesphere.com/paper/PMC12829097