Cardiovascular Genomics //
Science

Major research interests - gene regulatory mechanisms governing atherogenesis

Coronary artery disease (CAD) is the leading cause of death in the Western world. To improve CAD prevention, diagnosis and treatment, we need to gain better understanding of the gene regulatory and genetic factors that promote its progression. Especially, we are still far from understanding how different cell types such as endothelial cells (ECs), macrophages (Mɸs) and smooth muscle cells (SMCs) in the developing lesion contribute to the disease. In addition, accumulation of lipids and chronic inflammation are hallmarks of CAD and there is a clear consensus that liver, through regulation of cholesterol homeostasis, and dysfunctional adipose tissue may directly influence the function of cells of the vessel wall.

In this study, we first aim to decipher the cell-type specific contribution of ECs, Mɸs and SMCs in CAD progression by characterizing the gene regulatory processes that take place at the level of chromatin organization, transcription, post-transcription and translation in response to proartherogenic stimuli. The data gained here is used to identify gene regulatory mechanisms responsible for the altered expression of atherosclerosis risk genes and to construct a model of gene regulation during CAD development. Secondly, we aim to bring the functional characterization of genetic variants associated with CAD to date by identifying and interpreting the role of enhancer variants across all five disease relevant cell types. As majority of CAD-variants are located within these noncoding regulatory regions, establishing causal relationships between enhancer activity and coding gene expression can be used to translate genetic signals into biological mechanisms that could further lead to prognostic, diagnostic and therapeutic advances. Altogether, these two projects hold promise in obtaining a more complete picture of gene regulatory programs and causal events driving CAD development.

Funding

Academy of Finland, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, Diabetes Research Foundation

Selected publications

  1. Niskanen H, Tuszynska I, Zaborowski R, Heinäniemi M, Ylä-Herttuala S, Wilczynski B, Kaikkonen MU. Endothelial cell differentiation is encompassed by changes in long range interactions between inactive chromatin regions. Nucleic Acids Res. 2017 Dec 4 https://doi.org/10.1093/nar/gkx1214
  2. Bouvy-Liivrand M, Hernández de Sande A, Pölönen P, Mehtonen J, Vuorenmaa T, Niskanen H, Sinkkonen L, Heinäniemi M*, Kaikkonen MU*. Analysis of primary microRNA loci from nascent transcriptomes reveals regulatory domains governed by chromatin architecture. Nucleic Acids Res 2017 gkx680.  https://doi.org/10.1093/nar/gkx680
  3. López Rodríguez M, Kaminska D, Lappalainen K, Pihlajamäki J, Laakso M*, Kaikkonen MU*. Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells. Genome Med. 2017 Jul 6;9(1):63. https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0453-x
  4. Kaikkonen MU, Halonen P, Liu OH, Turunen TA, Pajula J, Moreau P, Selvarajan I, Tuomainen T, Aavik E, Tavi P, Ylä-Herttuala S. Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction.  Circ Cardiovasc Genet. 2017 Jun;10(3). pii: e001702. http://circgenetics.ahajournals.org/content/10/3/e001702.long

  5. Kaikkonen MU, Niskanen H, Romanoski CE, Kansanen E, Kivelä AM, Laitalainen J, Heinz S, Benner C, Glass CK, Ylä-Herttuala S. Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization. Nucleic Acids Research 2014 42(20):12570-84
  6. Oishi Y, Spann NJ, Link VM, Muse ED, Strid T, Edillor C, Kolar MJ, Matsuzaka T, Hayakawa S, Tao J, Kaikkonen MU, Carlin AF, Lam MT, Manabe I, Shimano H, Saghatelian A, Glass CK. SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism. Cell Metab. 2017 Feb 7;25(2):412-427. http://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30588-5?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413116305885%3Fshowall%3Dtrue
  7. Heinz S*, Romanoski CE* , Benner C, Allison KA, Kaikkonen MU, Orozco LD, Glass CK. Effect of natural genetic variation on enhancer selection and function. Nature 2013 Nov 28;503(7477):487-92.
  8. Kaikkonen MU*, Spann N*, Heinz S, Romanoski CE, Allison KA, Stender JD, Chun HB, Tough DF, Prinjha RK, BennerC and Glass CK. Remodeling of the enhancer landscape during macrophage activation is linked to enhancer transcription. Molecular Cell, 2013, Aug ;51(3): 310-325
  9. Lam MTY, Cho H, Lesch HP, Heinz S, Tanaka-Oishi Y, Benner C, Kaikkonen MU, Salim A, Kosaka M, Lee CY, Watt A, Grossman T, Rosenfeld MG, Evans RM, Glass CK. Rev-Erbs negatively regulate macrophage gene expression by repressing enhancer-directed transcription. Nature, 2013 Jun;498 (7455):511-5.
  10. Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, Qiu J, Liu W, Kaikkonen MU, Ohgi KA, Glass CK, Rosenfeld MG, Fu XD. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature. 2011 May 15;474(7351):390-4.