Cardiovascular Genomics //
Science

Major research interests - gene regulatory mechanisms governing atherogenesis

Atherosclerotic cardiovascular diseases are the leading cause of death in the Western world. It is thus of key importance to identify factors that promote the progression of atherosclerosis i.e. atherogenesis. The early events of atherogenesis take place in the endothelium, where internalisation of low density lipoproteins (LDL) in the intima results in endothelial cell (EC) dysfunction, expression of chemokines and monocyte recruitment. The majority of monocytes differentiate into macrophages (Mɸs) which after ingestion of oxidized LDL turn into foam cells that perpetuate the vascular remodeling. Inflammatory mediators released during the process induce a phenotype change of vascular smooth muscle cells (SMC) from the sessile phenotype to a proliferative synthetic state that contributes to the progression of vascular lesions.

Despite intense efforts to determine the role of ECs, Mɸs and SMCs in atherogenesis, we are far from understanding what makes these cells different and how do the differences in the cellular responses contribute to the disease process. This is largely due to a lack of knowledge of how transcriptional programs differ between cell types and a lack of comprehensive models of gene expression which integrate data from all levels of gene regulation. This study aims to identify the gene regulatory processes that take place in ECs, Mɸs and SMCs during atherogenesis by applying state-of-the-art next-generation sequencing methods (see figure below). We aim to untangle the complexity of gene regulatory processes at the transcriptional, post-transcriptional and translational level during atherogenesis i) in mouse and human primary cells in vitro and ii) in a mouse atherosclerosis model in vivo and iii) to study the effects of proatherogenic stimuli and genetic variation on chromatin organization. This research strives for fundamental discoveries that will advance our knowledge of atherogenesis and pave a route towards enhanced therapies and diagnostics.  

Funding

Academy of FinlandSigrid Jusélius Foundation, Finnish Cultural Foundation, Finnish Foundation for Cardiovascular Research

Selected publications

  1. 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
  2. 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
  3. 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

  4. 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
  5. 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
  6. 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.
  7. Li P*, Spann NJ*, Kaikkonen MU, Lu M, Oh DY, Fox JN, Bandyopadhyay G, Talukdar S, Xu J, Lagakos WS, Patsouris D, Armando A, Quehenberger O, Dennis EA, Watkins SM, Auwerx J, Glass CK, Olefsky JM. NCoR Repression of LXRs Restricts Macrophage Biosynthesis of Insulin-Sensitizing Omega 3 Fatty Acids. Cell. 2013 Sep 26;155(1):200-14
  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.