Top

Published in:

Open Access 01-02-2021 | Epigenetics | Original Paper

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells

Authors: Carlotta Tacconi, Yuliang He, Luca Ducoli, Michael Detmar

Published in: Angiogenesis | Issue 1/2021

Abstract

Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vascular ECs is regulated at the transcriptional level during development, the key molecular mechanisms governing their lineage identity under physiological or pathological conditions remain poorly understood. To explore the epigenomic signatures in the maintenance of EC lineage specificity, we compared the transcriptomic landscapes, histone composition (H3K4me3 and H3K27me3) and DNA methylomes of cultured matched human primary dermal lymphatic and blood vascular ECs. Our findings reveal that blood vascular lineage genes manifest a more ‘repressed’ histone composition in lymphatic ECs, whereas DNA methylation at promoters is less linked to the differential transcriptomes of lymphatic versus blood vascular ECs. Meta-analyses identified two transcriptional regulators, BCL6 and MEF2C, which potentially govern endothelial lineage specificity. Notably, the blood vascular endothelial lineage markers CD34, ESAM and FLT1 and the lymphatic endothelial lineage markers PROX1, PDPN and FLT4 exhibited highly differential epigenetic profiles and responded in distinct manners to epigenetic drug treatments. The perturbation of histone and DNA methylation selectively promoted the expression of blood vascular endothelial markers in lymphatic endothelial cells, but not vice versa. Overall, our study reveals that the fine regulation of lymphatic and blood vascular endothelial transcriptomes is maintained via several epigenetic mechanisms, which are crucial to the maintenance of endothelial cell identity.

Available only for authorised users

Bautch VL, Caron KM (2015) Blood and lymphatic vessel formation. Cold Spring Harb Perspect Biol 7(3):a008268. https://doi.org/10.1101/cshperspect.a008268CrossRefPubMedPubMedCentral

Cueni LN, Detmar M (2006) New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 126(10):2167–2177. https://doi.org/10.1038/sj.jid.5700464CrossRefPubMed

Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G (2002) An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. Embo J 21(7):1505–1513. https://doi.org/10.1093/emboj/21.7.1505CrossRefPubMedPubMedCentral

Welsh JD, Kahn ML, Sweet DT (2016) Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation. Blood 128(9):1169–1173. https://doi.org/10.1182/blood-2016-04-636415CrossRefPubMed

Hong YK, Detmar M (2003) Prox1, master regulator of the lymphatic vasculature phenotype. Cell Tissue Res 314(1):85–92. https://doi.org/10.1007/s00441-003-0747-8CrossRefPubMed

Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dynam 225(3):351–357. https://doi.org/10.1002/dvdy.10163CrossRef

Yang Y, Oliver G (2014) Development of the mammalian lymphatic vasculature. J Clin Invest 124(3):888–897. https://doi.org/10.1172/Jci71609CrossRefPubMedPubMedCentral

Jha SK, Rauniyar K, Jeltsch M (2018) Key molecules in lymphatic development, function, and identification. Ann Anat 219:25–34. https://doi.org/10.1016/j.aanat.2018.05.003CrossRefPubMed

Dejana E, Hirschi KK, Simons M (2017) The molecular basis of endothelial cell plasticity. Nat Commun. https://doi.org/10.1038/ncomms14361CrossRefPubMedPubMedCentral

10.

Ma WS, Oliver G (2017) Lymphatic endothelial cell plasticity in development and disease. Physiology 32(6):444–452. https://doi.org/10.1152/physiol.00015.2017CrossRefPubMedPubMedCentral

11.

Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, Waltari M, Hellstrom M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Yla-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454(7204):656–U668. https://doi.org/10.1038/nature07083CrossRefPubMed

12.

Valtola R, Salven P, Heikkila P, Taipale J, Joensuu H, Rehn M, Pihlajaniemi T, Weich H, deWaal R, Alitalo K (1999) VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol 154(5):1381–1390. https://doi.org/10.1016/S0002-9440(10)65392-8CrossRefPubMedPubMedCentral

13.

Ladstatter S, Tachibana K (2019) Genomic insights into chromatin reprogramming to totipotency in embryos. J Cell Biol 218(1):70–82. https://doi.org/10.1083/jcb.201807044CrossRefPubMedPubMedCentral

14.

Stylianou E (2019) Epigenetics of chronic inflammatory diseases. J Inflamm Res 12:1–14. https://doi.org/10.2147/Jir.S129027CrossRefPubMed

15.

Poli V, Fagnocchi L, Zippo A (2018) Tumorigenic cell reprogramming and cancer plasticity: interplay between signaling, microenvironment, and epigenetics. Stem Cells Int. https://doi.org/10.1155/2018/4598195CrossRefPubMedPubMedCentral

16.

Schlereth K, Weichenhan D, Bauer T, Heumann T, Giannakouri E, Lipka D, Jaeger S, Schlesner M, Aloy P, Eils R, Plass C, Augustin HG (2018) The transcriptomic and epigenetic map of vascular quiescence in the continuous lung endothelium. Elife. https://doi.org/10.7554/eLife.34423CrossRefPubMedPubMedCentral

17.

Sabbagh MF, Heng JS, Luo C, Castanon RG, Nery JR, Rattner A, Goff LA, Ecker JR, Nathans J (2018) Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells. Elife. https://doi.org/10.7554/eLife.36187CrossRefPubMedPubMedCentral

18.

Hirakawa S, Hong YK, Harvey N, Schacht V, Matsuda K, Libermann T, Detmar M (2003) Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162(2):575–586. https://doi.org/10.1016/S0002-9440(10)63851-5CrossRefPubMedPubMedCentral

19.

Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. Embo J 21(17):4593–4599. https://doi.org/10.1093/emboj/cdf470CrossRefPubMedPubMedCentral

20.

Bronneke S, Bruckner B, Peters N, Bosch TCG, Stab F, Wenck H, Hagemann S, Winnefeld M (2012) DNA methylation regulates lineage-specifying genes in primary lymphatic and blood endothelial cells. Angiogenesis 15(2):317–329. https://doi.org/10.1007/s10456-012-9264-2CrossRefPubMed

21.

Shirodkar AV, St Bernard R, Gavryushova A, Kop A, Knight BJ, Yan MS, Man HS, Sud M, Hebbel RP, Oettgen P, Aird WC, Marsden PA (2013) A mechanistic role for DNA methylation in endothelial cell (EC)-enriched gene expression: relationship with DNA replication timing. Blood 121(17):3531–3540. https://doi.org/10.1182/blood-2013-01-479170CrossRefPubMedPubMedCentral

22.

Barrero MJ, Boue S, Belmonte JCI (2010) Epigenetic mechanisms that regulate cell identity. Cell Stem Cell 7(5):565–570. https://doi.org/10.1016/j.stem.2010.10.009CrossRefPubMed

23.

Plass C, Pfister SM, Lindroth AM, Bogatyrova O, Claus R, Lichter P (2013) Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat Rev Genet 14(11):765–780. https://doi.org/10.1038/nrg3554CrossRefPubMed

24.

Hyun K, Jeon J, Park K, Kim J (2017) Writing, erasing and reading histone lysine methylations. Exp Mol Med. https://doi.org/10.1038/emm.2017.11CrossRefPubMedPubMedCentral

25.

Ruthenburg AJ, Allis CD, Wysocka J (2007) Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25(1):15–30. https://doi.org/10.1016/j.molcel.2006.12.014CrossRefPubMed

26.

Saksouk N, Simboeck E, Dejardin J (2015) Constitutive heterochromatin formation and transcription in mammals. Epigenetics Chromatin 8:3. https://doi.org/10.1186/1756-8935-8-3CrossRefPubMedPubMedCentral

27.

Paksa A, Rajagopal J (2017) The epigenetic basis of cellular plasticity. Curr Opin Cell Biol 49:116–122. https://doi.org/10.1016/j.ceb.2018.01.003CrossRefPubMed

28.

Kim M, Costello J (2017) DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med. https://doi.org/10.1038/emm.2017.10CrossRefPubMedPubMedCentral

29.

Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13(7):484–492. https://doi.org/10.1038/nrg3230CrossRefPubMed

30.

Melamed P, Yosefzon Y, Rudnizky S, Pnueli L (2016) Transcriptional enhancers: transcription, function and flexibility. Transcr-Austin 7(1):26–31. https://doi.org/10.1080/21541264.2015.1128517CrossRef

31.

Anastasiadi D, Esteve-Codina A, Piferrer F (2018) Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species. Epigenet Chromatin. https://doi.org/10.1186/s13072-018-0205-1CrossRef

32.

Zhao X, Sternsdorf T, Bolger TA, Evans RM, Yao TP (2005) Regulation of MEF2 by histone deacetylase 4-and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol 25(19):8456–8464. https://doi.org/10.1128/Mcb.25.19.8456-8464.2005CrossRefPubMedPubMedCentral

33.

Haberland M, Arnold MA, McAnally J, Phan D, Kim Y, Olson EN (2007) Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation. Mol Cell Biol 27(2):518–525. https://doi.org/10.1128/Mcb.01415-06CrossRefPubMed

34.

Zhang H, Okada S, Hatano M, Okabe S, Tokuhisa T (2001) A new functional domain of Bcl6 family that recruits histone deacetylases. Bba-Mol Cell Res 1540(3):188–200. https://doi.org/10.1016/S0167-4889(01)00128-8CrossRef

35.

Lemercier C, Brocard MP, Puvion-Dutilleul F, Kao HY, Albagli O, Khochbin S (2002) Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor. J Biol Chem 277(24):22045–22052. https://doi.org/10.1074/jbc.M201736200CrossRefPubMed

36.

McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A, Diaz E, LaFrance LV, Mellinger M, Duquenne C, Tian XR, Kruger RG, McHugh CF, Brandt M, Miller WH, Dhanak D, Verma SK, Tummino PJ, Creasy CL (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492(7427):108. https://doi.org/10.1038/nature11606CrossRefPubMed

37.

Zgraggen S, Ochsenbein AM, Detmar M (2013) An important role of blood and lymphatic vessels in inflammation and allergy. J Allergy (Cairo) 2013:672381. https://doi.org/10.1155/2013/672381CrossRef

38.

Ruddell A, Croft A, Kelly-Spratt K, Furuya M, Kemp CJ (2014) Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads. BMC Cancer 14:354. https://doi.org/10.1186/1471-2407-14-354CrossRefPubMedPubMedCentral

39.

Karaman S, Detmar M (2014) Mechanisms of lymphatic metastasis. J Clin Invest 124(3):922–928. https://doi.org/10.1172/JCI71606CrossRefPubMedPubMedCentral

40.

Kass SU, Landsberger N, Wolffe AP (1997) DNA methylation directs a time-dependent repression of transcription initiation. Curr Biol 7(3):157–165. https://doi.org/10.1016/s0960-9822(97)70086-1CrossRefPubMed

41.

Gross JA, Pacis A, Chen GG, Drupals M, Lutz PE, Barreiro LB, Turecki G (2017) Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals. Transl Psychiatry. https://doi.org/10.1038/tp.2017.93CrossRefPubMedPubMedCentral

42.

Wong BW, Zecchin A, Garcia-Caballero M, Carmeliet P (2018) Emerging concepts in organ-specific lymphatic vessels and metabolic regulation of lymphatic development. Dev Cell 45(3):289–301. https://doi.org/10.1016/j.devcel.2018.03.021CrossRefPubMed

43.

Johnson NC, Dillard ME, Baluk P, McDonald DM, Harvey NL, Frase SL, Oliver G (2008) Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Gene Dev 22(23):3282–3291. https://doi.org/10.1101/gad.1727208CrossRefPubMedPubMedCentral

44.

Cueni LN, Chen L, Zhang H, Marino D, Huggenberger R, Alitalo A, Bianchi R, Detmar M (2010) Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin. Blood 116(20):4376–4384. https://doi.org/10.1182/blood-2010-04-278564CrossRefPubMedPubMedCentral

45.

Riedl J, Preusser M, Nazari PMS, Posch F, Panzer S, Marosi C, Birner P, Thaler J, Brostjan C, Lotsch D, Berger W, Hainfellner JA, Pabinger I, Ay C (2017) Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. Blood 129(13):1831–1839. https://doi.org/10.1182/blood-2016-06720714CrossRefPubMed

46.

Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K (2000) Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 156(5):1499–1504. https://doi.org/10.1016/S0002-9440(10)65021-3CrossRefPubMedPubMedCentral

47.

Witmer AN, van Blijswijk BC, Dai J, Hofman P, Partanen TA, Vrensen GFJM, Schlingemann RO (2001) VEGFR-3 in adult angiogenesis. J Pathol 195(4):490–497. https://doi.org/10.1002/path.969CrossRefPubMed

48.

Ehrlich KC, Paterson HL, Lacey M, Ehrlich M (2016) DNA hypomethylation in intragenic and intergenic enhancer chromatin of muscle-specific genes usually correlates with their expression. Yale J Biol Med 89(4):441–455PubMedPubMedCentral

49.

Fleischer T, Tekpli X, Mathelier A, Wang SX, Nebdal D, Dhakal HP, Sahlberg KK, Schlichting E, Borresen-Dale AL, Borgen E, Naume B, Eskeland R, Frigessi A, Tost J, Hurtado A, Kristensen VN, OS OBCRC (2017) DNA methylation at enhancers identifies distinct breast cancer lineages. Nat Commun. https://doi.org/10.1038/s41467-017-00510-xCrossRefPubMedPubMedCentral

50.

Rinaldi L, Datta D, Serrat J, Morey L, Solanas G, Avgustinova A, Blanco E, Pons JI, Matallanas D, Von Kriegsheim A, Di Croce L, Benitah SA (2016) Dnmt3a and Dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis. Cell Stem Cell 19(4):491–501. https://doi.org/10.1016/j.stem.2016.06.020CrossRefPubMed

51.

Fan Y, Wang Y, Tang Z, Zhang H, Qin X, Zhu Y, Guan Y, Wang X, Staels B, Chien S, Wang N (2008) Suppression of pro-inflammatory adhesion molecules by PPAR-delta in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 28(2):315–321. https://doi.org/10.1161/ATVBAHA.107.149815CrossRefPubMed

52.

Buchberger E, Payrhuber D, El Harchi M, Zagrapan B, Scheuba K, Zommer A, Bugyik E, Dome B, Kral JB, Schrottmaier WC, Schabbauer G, Petzelbauer P, Groger M, Bilban M, Brostjan C (2017) Inhibition of the transcriptional repressor complex Bcl-6/BCoR induces endothelial sprouting but does not promote tumor growth. Oncotarget 8(1):552–564. https://doi.org/10.18632/oncotarget.13477CrossRefPubMed

53.

Wang DZ, Valdez MR, McAnally J, Richardson J, Olson EN (2001) The Mef2c gene is a direct transcriptional target of myogenic bHLH and MEF2 proteins during skeletal muscle development. Development 128(22):4623–4633PubMed

54.

Lin Q, Lu JR, Yanagisawa H, Webb R, Lyons GE, Richardson JA, Olson EN (1998) Requirement of the MADS-box transcription factor MEF2C for vascular development. Development 125(22):4565–4574PubMed

55.

Francois M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, Cheah KSE, Stacker SA, Muscat GEO, Achen MG, Dejana E, Koopman P (2008) Sox18 induces development of the lymphatic vasculature in mice. Nature 456(7222):643–669. https://doi.org/10.1038/nature07391CrossRefPubMed

56.

Park DY, Lee J, Park I, Choi D, Lee S, Song S, Hwang Y, Hong KY, Nakaoka Y, Makinen T, Kim P, Alitalo K, Hong YK, Koh GY (2014) Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity. J Clin Invest 124(9):3960–3974. https://doi.org/10.1172/Jci75392CrossRefPubMedPubMedCentral

57.

Maejima T, Inoue T, Kanki Y, Kohro T, Li G (2014) Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells (vol 9, e96005, 2014). PLoS ONE. https://doi.org/10.1371/journal.pone.0099749CrossRefPubMedPubMedCentral

58.

Hosking BM, Wang SCM, Chen SL, Penning S, Koopman P, Muscat GEO (2001) SOX18 directly interacts with MEF2C in endothelial cells. Biochem Bioph Res Co 287(2):493–500. https://doi.org/10.1006/bbrc.2001.5589CrossRef

59.

Messenguy F, Dubois E (2003) Role of MADS box proteins and their cofactors in combinatorial control of gene expression and cell development. Gene 316:1–21. https://doi.org/10.1016/S0378-1119(03)00747-9CrossRefPubMed

60.

Amatschek S, Kriehuber E, Bauer W, Reininger B, Meraner P, Wolpl A, Schweifer N, Haslinger C, Stingl G, Maurer D (2007) Blood and lymphatic endothelial cell-specific differentiation programs are stringently controlled by the tissue environment. Blood 109(11):4777–4785. https://doi.org/10.1182/blood-2006-10-053280CrossRefPubMed

61.

Wick N, Saharinen P, Saharinen J, Gurnhofer E, Steiner CW, Raab I, Stokic D, Giovanoli P, Buchsbaum S, Burchard A, Thurner S, Alitalo K, Kerjaschki D (2007) Transcriptomal comparison of human dermal lymphatic endothelial cells ex vivo and in vitro. Physiol Genomics 28(2):179–192. https://doi.org/10.1152/physiolgenomics.00037.2006CrossRefPubMed

62.

Sabbagh MF, Nathans J (2020) A genome-wide view of the de-differentiation of central nervous system endothelial cells in culture. Elife. https://doi.org/10.7554/eLife.51276CrossRefPubMedPubMedCentral

63.

Magnusson M, Larsson P, Lu EX, Bergh N, Caren H, Jern S (2016) Rapid and specific hypomethylation of enhancers in endothelial cells during adaptation to cell culturing. Epigenetics 11(8):614–624. https://doi.org/10.1080/15592294.2016.1192734CrossRefPubMedPubMedCentral

64.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635CrossRefPubMed

65.

Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26(6):841–842. https://doi.org/10.1093/bioinformatics/btq033CrossRefPubMedPubMedCentral

66.

Liao Y, Smyth GK, Shi W (2019) The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Res. https://doi.org/10.1093/nar/gkz114CrossRefPubMedPubMedCentral

67.

Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. https://doi.org/10.1186/s13059-014-0550-8CrossRefPubMedPubMedCentral

68.

Langmead B, Salzberg SL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9(4):357–U354. https://doi.org/10.1038/Nmeth.1923CrossRefPubMedPubMedCentral

69.

Ramirez F, Ryan DP, Gruning B, Bhardwaj V, Kilpert F, Richter AS, Heyne S, Dundar F, Manke T (2016) deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res 44(W1):W160–W165. https://doi.org/10.1093/nar/gkw257CrossRefPubMedPubMedCentral

70.

Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nussbaum C, Myers RM, Brown M, Li W, Liu XS (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol. https://doi.org/10.1186/gb-2008-9-9-r137CrossRefPubMedPubMedCentral

71.

Robinson JT, Thorvaldsdottir H, Wenger AM, Zehir A, Mesirov JP (2017) Variant review with the integrative genomics viewer. Cancer Res 77(21):E31–E34. https://doi.org/10.1158/0008-5472.Can-17-0337CrossRefPubMedPubMedCentral

72.

Yu GC, Wang LG, He QY (2015) ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics 31(14):2382–2383. https://doi.org/10.1093/bioinformatics/btv145CrossRefPubMed

73.

Stark R, Brown G (2011) DiffBind: differential binding analysis of ChIPSeq peak data. Bioconductor. https://doi.org/10.18129/B9.bioc.DiffBindCrossRef

74.

Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ, Brown GD, Gojis O, Ellis IO, Green AR, Ali S, Chin SF, Palmieri C, Caldas C, Carroll JS (2012) Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481(7381):389–393. https://doi.org/10.1038/nature10730CrossRefPubMedPubMedCentral

75.

Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1):139–140. https://doi.org/10.1093/bioinformatics/btp616CrossRefPubMed

76.

McCarthy DJ, Chen Y, Smyth GK (2012) Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res 40(10):4288–4297. https://doi.org/10.1093/nar/gks042CrossRefPubMedPubMedCentral

77.

Moran S, Arribas C, Esteller M (2016) Validation of a DNA methylation microarray for 850,000 CpG sites of the human genome enriched in enhancer sequences. Epigenomics 8(3):389–399. https://doi.org/10.2217/epi.15.114CrossRefPubMed

78.

Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA (2014) Minfi: a flexible and comprehensive bioconductor package for the analysis of infinium DNA methylation microarrays. Bioinformatics 30(10):1363–1369. https://doi.org/10.1093/bioinformatics/btu049CrossRefPubMedPubMedCentral

79.

McCartney DL, Walker RM, Morris SW, McIntosh AM, Porteous DJ, Evans KL (2016) Identification of polymorphic and off-target probe binding sites on the Illumina Infinium MethylationEPIC BeadChip. Genom Data 9:22–24. https://doi.org/10.1016/j.gdata.2016.05.012CrossRefPubMedPubMedCentral

80.

Pidsley R, Zotenko E, Peters TJ, Lawrence MG, Risbridger GP, Molloy P, Van Djik S, Muhlhausler B, Stirzaker C, Clark SJ (2016) Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling. Genome Biol. https://doi.org/10.1186/s13059-016-1066-1CrossRefPubMedPubMedCentral

81.

Ritchie ME, Phipson B, Wu D, Hu YF, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. https://doi.org/10.1093/nar/gkv007CrossRefPubMedPubMedCentral

82.

Peters TJ, Buckley MJ, Statham AL, Pidsley R, Samaras K, Lord RV, Clark SJ, Molloy PL (2015) De novo identification of differentially methylated regions in the human genome. Epigenet Chromatin. https://doi.org/10.1186/1756-8935-8-6CrossRef

83.

Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38(4):576–589. https://doi.org/10.1016/j.molcel.2010.05.004CrossRefPubMedPubMedCentral

Title: Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells
Authors: Carlotta Tacconi
Yuliang He
Luca Ducoli
Michael Detmar
Publication date: 01-02-2021
Publisher: Springer Netherlands
Keyword: Epigenetics
Published in: Angiogenesis / Issue 1/2021
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-020-09743-9

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

Piwi-interacting RNAs (piRNAs) as potential biomarkers and therapeutic targets for cardiovascular diseases

Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

Characterization of a neutralizing anti-human galectin-1 monoclonal antibody with angioregulatory and immunomodulatory activities

Vessel tech: a high-accuracy pipeline for comprehensive mouse retinal vasculature characterization

Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage