Henri Niskanen

Max Planck Institute for Molecular Genetics | MOLGEN · Department of Genome Regulation

Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection re...

Aims Vascular smooth muscle cells (SMCs) and their derivatives are key contributors to the development of atherosclerosis. However, studying changes in SMC gene expression in heterogeneous vascular tissues is challenging due to the technical limitations and high cost associated with current approaches. In this paper, we apply translating ribosome a...

Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection re...

Impaired oxygen homeostasis is a frequently encountered pathophysiological factor in multiple complex diseases, including cardiovascular disease and cancer. While the canonical hypoxia response pathway is well characterized, less is known about the role of noncoding RNAs in this process. Here, we investigated the nascent and steady-state noncoding...

Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into the genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways, and genes to disease heritability. Here, we investigate the biological diversity of atheroscl...

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1–3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates...

Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV derepression is associated with lethality during early development has been a mystery. Here, we report that rapid and selective degradation of the heterochromatin adapter protein TRIM28 triggers dissociation of transcriptional condensates from loc...

Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways and genes to disease heritability. Here, we investigate the biological diversity of atherosclerosi...

Endogenous retroviruses (ERVs) comprise ~10% of mammalian genomes, and ERVs are repressed by multiple cellular mechanisms including heterochromatin, DNA methylation, and methylation of their RNA transcripts 1-13. Although the vast majority of ERVs in mammals are incapable of retrotransposition, ERV de-repression during early development is associat...

Super-enhancers are clusters of enhancers associated with cell lineage. They can be powerful gene-regulators and may be useful in cell-type specific viral-vector development. Here, we have screened for endothelial super-enhancers and identified an enhancer from within a cluster that conferred 5–70-fold increase in transgene expression. Importantly,...

Background Microfold cells (M cells) are immunosurveillance epithelial cells located in the Peyer’s patches (PP’s) in the intestine responsible for monitoring and transcytosis of antigens, microorganisms and pathogens. Mature Microfold cells employ the receptor Glyoprotein 2 (Gp2) to aid in transcytosis. Recent studies have revealed transcription f...

Vascular endothelial growth factors (VEGFs) are best known as key regulators of angiogenesis and lymphangiogenesis. Although VEGFs have been promising therapeutic targets for various cardiovascular related diseases, their regulatory landscape in endothelial cells remains elusive. Several studies have highlighted the involvement of non-coding RNAs (...

The BMP/TGFβ-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-H...

Tamoxifen is the most prescribed selective estrogen receptor (ER) modulator in patients with ER-positive breast cancers. Tamoxifen requires the transcription factor paired box 2 protein (PAX2) to repress the transcription of ERBB2/HER2. Now, we identified that PAX2 inhibits cell growth of ER+/HER2− tumor cells in a dose-dependent manner. Moreover,...

Aims Oxidized phospholipids and microRNAs (miRNAs) are increasingly recognized to play a role in endothelial dysfunction driving atherosclerosis. NRF2 transcription factor is one of the key mediators of the effects of oxidized phospholipids, but the gene regulatory mechanisms underlying the process remain obscure. Here, we investigated the genome-w...

Expansions of amino acid repeats occur in >20 inherited human disorders, and many occur in intrinsically disordered regions (IDRs) of transcription factors (TFs). Such diseases are associated with protein aggregation, but the contribution of aggregates to pathology has been controversial. Here, we report that alanine repeat expansions in the HOXD13...

Background: High grade serous ovarian carcinoma (HGSOC) is the most common subtype of epithelial ovarian cancers (EOC) with poor prognosis. In most cases EOC is widely disseminated at the time of diagnosis. Despite the optimal cytoreductive surgery and chemotherapy most patients develop chemoresistance, and the 5-year overall survival being only 2...

Hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells (iPSCs) provide a renewable source of cells for drug discovery, disease modelling and cell-based therapies. Here, by using GRO-Seq we provide the first genome-wide analysis of the nascent RNAs in iPSCs, HLCs and primary hepatocytes to extend our understanding of the transcript...

Hypoxia occurs in human atherosclerotic lesions and has multiple adverse effects on endothelial cell metabolism. Recently, key roles of long non-coding RNAs (lncRNAs) in the development of atherosclerosis have begun to emerge. In this study, we investigate the lncRNA profiles of human umbilical vein endothelial cells subjected to hypoxia using glob...

Statins are effective drugs used to prevent and treat cardiovascular diseases but their effects in the absence of low density lipoprotein receptor (LDLR) and on the risk of diabetes are not yet well characterized. The aim of this study was to clarify systemic and pleiotropic effects of rosuvastatin on cardiovascular and diabetic phenotypes. IGF-II/...

Objective- Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained...

Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that...

Endothelial cell (EC) therapy may promote vascular growth or reendothelization in a variety of disease conditions. However, the production of a cell therapy preparation containing differentiated, dividing cells presenting typical EC phenotype, functional properties and chemokine profile is challenging. We focused on comparative analysis of seven sm...

EC differentiation duration from iPSC was tested by monitoring of ECmarker expression up to 36 days. A presentative diagram of differentiation group RT showing howEC marker expression goes up until differentiation day 15–16 and down after that. ECs lose theirphenotype in a longer culturing period in all tested differentiation groups.

Heatmap of normalized RPKM values (−1 to 1) of the 50 most highly expressed transcription factors in HUVECs and HAECs. Clustering was performed for genes and samples using Spearman's rank correlation (complete linkage).

Gene expression analysis comparing hiPSCs to treatment groups on day 5 and day 15. Normalized gene expression values are provided with log2 FC and FDR values for each pairwise comparison.

Principal component analysis (PCA) of log-transformed RPKM valuesfrom (A) all RNA-Seq samples (2D plot) and (B) all samples subjected to 15 day differentiationregimen (3D plot).

Mechanistic networks generated by IPA for transcription factors SMARCA4, GATA6 and KMT2A predicted to be activated from Figure 6B. Blue depicts predicted inhibition and orange activation. The tones of color indicate confidence level (light = low confidence; dark = high confidence).

Mechanistic networks generated by IPA for a chemical compoundtretinoin predicted to be activated. Blue depicts predicted inhibition and orange activation. The tonesof color indicate confidence level (light = low confidence; dark = high confidence).

Endothelial cells (ECs) differentiate from mesoder-mal progenitors during vasculogenesis. By comparing changes in chromatin interactions between human umbilical vein ECs, embryonic stem cells and mesendoderm cells, we identified regions exhibiting EC-specific compartmentalization and changes in the degree of connectivity within topologically associ...

Changes in mature microRNA (miRNA) levels that occur downstream of signaling cascades play an important role during human development and disease. However, the regulation of primary microRNA (pri-miRNA) genes remains to be dissected in detail. To address this, we followed a data-driven approach and developed a transcript identification, validation...

Changes in mature microRNA (miRNA) levels that occur downstream of signaling cascades play an important role during human development and disease. However, the regulation of primary microRNA (pri-miRNA) genes remains to be dissected in detail. To address this, we followed a data-driven approach and developed a transcript identification, validation...

Identified topologically associated domains.The chromosomal coordinates (hg19) of TADs with breakpoints and all TADs as identified based on HiC data are reported. The number and frequency of breakpoints, together with% of domain spanned by convT are given for TADs with breakpoints. The highlighted rows correspond to TADs shown in Figure 1 and Figur...

Identified convT and Pol2 stalling regions.Regions with transcription from both strands (convT) or change points in the intragenic signal (Pol2 stalling sites) identified from B-lineage cells (REH, Nalm6 and Lymphoblastoid) or ES cells are listed with coordinates in the hg19 human genome. Coordinates of putative enhancers in B-lineage cells based o...

Statistical analysis of separate DRIP-seq and DNAse-seq replicates.Statistical analysis is presented for the independent experiments used in the Wilcoxon rank sum tests. Related to Figures 3 and 4.DOI: http://dx.doi.org/10.7554/eLife.13087.020

Overlap of wide Pol2 stalling regions with unusually wide peaks representing other chromatin features.The table summarizes the highest observed odds ratios in the Fisher test for the overlap between top 5% widest chromatin features and 5% of widest Pol2 stalling regions. Empirical p-values are reported together with the Fisher test values separatel...

Intragenic recurrent SV in ETV6-RUNX1 patients with overlap to vulnerable regions. The patient and region identifiers for recurrent intragenic SV in ETV6-RUNX1 patients are listed, reporting separately those co-localized with Pol2 stalling or convT regions. DOI: http://dx.doi.org/10.7554/eLife.13087.033

Clinical data for patients with high AICDA expression. Study description, sample identifier, cytogenetic group, age and dataset identifier are listed for the patients within high AICDA expression level. Statistical analysis testing enrichment of detected AICDA expression in high risk studies is summarized in worksheet 2. DOI: http://dx.doi.org/10.7...

Breakpoint clustering to regions.ETV6-RUNX1 breakpoint data used in the analysis was divided into three categories based on evidence for RSS-guided RAG targeting to the region (RSS-motifs). To analyze recurrence, breakpoint events within 1-kb distance were stitched together. The resulting genomic region coordinates (hg19) and the number of breakpoi...

pre-B-ALL transcriptome samples.Sample identifiers of pre-B-ALL transcriptomes analyzed and their coordinates on the dimensionality reduction plot.DOI: http://dx.doi.org/10.7554/eLife.13087.029

GRO-seq sample summary. Description of the patient and cell line GRO-seq samples used in the analysis, including the cell culture conditions, replicate information and the total number of pooled sequencing reads obtained after quality filtering and alignment. A more detailed table for cultured samples with replicate information and accession codes...

Genomic coordinates for regions displayed. The coordinates of example gene regions displayed in the main and supplementary figures are listed (hg19 human genome version). DOI: http://dx.doi.org/10.7554/eLife.13087.031

Breakpoint hotspot analysis for genes binned by the transcription level. Hypergeometric test statistics for genes stratified by expression level. Breakpoint overlap with transcriptional features was tested within the binned intragenic regions. Data for ETV6-RUNX1 subtype and all pre-B-ALL subtypes are shown as separate worksheets. Related to Figure...

Custom blacklisted genomic regions. Blacklisted regions discarded from the analysis that were deemed to represent low-mappability, rRNA and snoRNA loci based on GRO-seq signal. Coordinates refer to the hg19 human genome version. DOI: http://dx.doi.org/10.7554/eLife.13087.035

ELife digest Some of the most common cancers found in children are called precursor leukemias, which may start to develop before birth. Cancerous cells often contain alterations to the genetic information in their DNA. In precursor leukemias, the most common genetic changes involve deleting, adding or rearranging segments of the DNA sequence. Sever...

Phorbol diester PMA (phorbol 12-myristate 13-acetate) is a well-known promoter of tumor progression. PMA also regulates cell adhesion by several mechanisms including conformational activation of integrins and integrin clustering. Here, PMA was shown to induce lamellipodia formation and reorganization of the adhesion sites as well as actin and vimen...

Vascular endothelial growth factor A (VEGF-A) is a master regulator of angiogenesis, vascular development and function. In this study we investigated the transcriptional regulation of VEGF-A-responsive genes in primary human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) using genome-wide global run-on sequenci...

Oxidative stress and inflammation are known to be associated with age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells play the principal role in the immune defense of macula, and their dysfunction is a crucial event leading to clinically relevant changes seen in AMD. In the present study, we have examined the ability of o...

We have analyzed the structure and function of the integrin α(1)I domain harboring a gain-of-function mutation E317A. To promote protein crystallization, a double variant with an additional C139S mutation was used. In cell adhesion assays, the E317A mutation promoted binding to collagen. Similarly, the double mutation C139S/E317A increased adhesion...