Cardiovascular Genomics //
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.
- Shaked I, Hanna RN, Shaked H, Chodaczek G, Nowyhed HN, Tweet G, Tacke R, Basat AB, Mikulski Z, Togher S, Miller J, Blatchley A, Salek-Ardakani S, Darvas M, Kaikkonen MU, Thomas GD, Lai-Wing-Sun S, Rezk A, Bar-Or A, Glass CK, Bandukwala H, Hedrick CC. Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation. Nature Immunology 2015 16(12):1228-34
- Niskanen EA, Malinen M, Sutinen P, Toropainen S, Paakinaho V, Vihervaara A, Joutsen J, Kaikkonen MU, Sistonen L, Palvimo JJ. Global SUMOylation on active chromatin is an acute heat stress response restricting transcription. Genome Biol. 2015 Jul 28;16:153.
- Roberts TC, Hart JR, Kaikkonen MU, Weinberg MS, Vogt PK, Morris KV. Quantification of nascent transcription by bromouridine immunocapture nuclear run-on RT-qPCR. Nat Protoc. 2015 Aug;10(8):1198-211.
- 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
- Allison KA, Kaikkonen MU, Gaasterland T, Glass CK. Vespucci: a system for building annotated databases of nascent transcripts. Nucleic Acids Res., 2014; 42(4):2433-47
- 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.
- 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
- 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
- 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.
- 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.