Christoforos Nikolaou

• BSc Chemistry, PhD Biology
• Professor (Assistant) at University of Crete

Cell fate instructive genes tend to be regulated by large clusters of enhancers. Whether and how individual enhancers within such clusters cooperate in regulating gene expression is poorly understood. We have previously developed a computational method, SEGCOND, which identifies hubs that we termed Putative Transcriptional Condensates (PTCs), consi...

The Promyelocytic Leukemia protein (PML) and its associated nuclear bodies have recently emerged as critical regulators of embryonic stem (ES) cell identity. Despite their recognized importance, the complete spectrum of PML-mediated molecular events in ES cells remains unclear. In this report we have studied how PML is shaping the proteomic and SUM...

Cell-fate instructive genes tend to be regulated by large clusters of enhancers. Whether and how individual enhancers within such clusters cooperate in regulating gene expression is poorly understood. We have previously developed a computational method, SEGCOND, that identifies hubs consisting of enhancer clusters and their target genes, termed Put...

Senescence —the endpoint of replicative lifespan for normal cells— is established via a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences, and functional purpose of SICCs remained unknown. Here, we combine fu...

Background A key feature of Systemic Lupus Erythematosus (SLE) is the female predominance, as women present with this disease 9-fold more than men. In addition, the phenotype of the disease in each sex is quite distinct. Hormone impact, genetic distance, differential microbiome and epigenetic mechanisms are thought to be the main reasons for this s...

One elusive aspect of the chromosome architecture is how it constrains the DNA topology. Nucleosomes stabilise negative DNA supercoils by restraining a DNA linking number difference (∆Lk) of about −1.26. However, whether this capacity is uniform across the genome is unknown. Here, we calculate the ∆Lk restrained by over 4000 nucleosomes in yeast ce...

Cellular senescence is acknowledged as a key contributor to organismal ageing and late‐life disease. Though popular, the study of senescence in vitro can be complicated by the prolonged and asynchronous timing of cells committing to it and by its paracrine effects. To address these issues, we repurposed a small molecule inhibitor, inflachromene (IC...

Substantial evidence highlights divergences in immune responses between men and women. Women are more susceptible to autoimmunity, whereas men suffer from the more severe presentation of autoimmune disorders. The molecular mechanism of this sexual dimorphism remains elusive. Herein, we conducted a comprehensive analysis of sex differences in whole-...

We had shown that administration of the senolytic Dasatinib abolishes arthritis in the human TNF transgenic mouse model of chronic destructive arthritis when given in combination with a sub-therapeutic dose of the anti-TNF mAb Infliximab (1mg/kg). Herein, we found that while the number of senescent chondrocytes (GL13+/Ki67-), assessed according to...

Promyelocytic leukemia protein (PML) modulates diverse cell functions that contribute to both tumor-suppressor and pro-oncogenic effects, depending on the cellular context. We show here that PML knockdown (KD) in MDA-MB-231, but not MCF7, breast cancer cells, prolonged stem-cell-like survival, and increased cell proliferation and migration, which i...

One fundamental yet elusive aspect of chromosome architecture is the topolome, which refers to how chromatin elements shape the path of DNA. Nucleosomes stabilise negative DNA supercoils, with most nucleosomes typically restraining a DNA linking number difference (∆Lk) of about -1.26. However, whether this capacity is uniform across the genome is u...

One fundamental yet elusive aspect of the chromosome architecture is the constrained topolome, which refers to how chromatin elements restrain DNA topology. Nucleosomes stabilise negative DNA supercoils, with most nucleosomes typically restraining a DNA linking number difference (ΔLk) of about -1.26. However, whether this capacity is uniform across...

Intergenic genomic regions have essential regulatory and structural roles that impose constraints on their sequences. But regions that do not currently encode proteins also carry the potential to do so in the future. De novo gene emergence, the evolution of novel genes out of previously non-coding sequences has now been established as a potent forc...

Early during preimplantation development and in heterogeneous mouse embryonic stem cells (mESC) culture, pluripotent cells are specified towards either the primed epiblast or the primitive endoderm (PE) lineage. Canonical Wnt signaling is crucial for safeguarding naive pluripotency and embryo implantation, yet the role and relevance of canonical Wn...

Nearly one third of Saccharomyces cerevisiae protein coding sequences correspond to duplicate genes, equally split between small-scale duplicates (SSD) and whole-genome duplicates (WGD). While duplicate genes have distinct properties compared to singletons, to date, there has been no systematic analysis of their positional preferences. In this work...

Promyelocytic Leukemia Protein (PML) is the core protein of nuclear bodies (NBs) that regulate a large number of cellular processes, including, context dependent, tumor-suppressor and pro-oncogenic effects. PML knockdown (KD) in breast cancer lines MDA-MB-231, but not MCF7, cells showed higher cell proliferation, increased migration properties and...

In addition to increasing the complexity of the transcriptional output, alternative RNA splicing can lead to the reduction of mRNA translation or the production of non-functional or malfunctional proteins, thus representing a vital component of the gene regulation process. Herein, we set out to detect and characterize alternative splicing events th...

Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes i...

Background Medications for Rheumatoid Arthritis (RA) have emerged in the last two decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes i...

Systemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulati...

Systemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulati...

Genes in linear proximity often share regulatory inputs, expression and evolutionary patterns, even in complex eukaryote genomes with extensive intergenic sequences. Gene regulation, on the other hand, is effected through the co-ordinated activation (or suppression) of genes participating in common biological pathways, which are often transcribed f...

Genes in linear proximity often share regulatory inputs, expression and evolutionary patterns, even in complex eukaryote genomes with extensive intergenic sequences. Gene regulation, on the other hand, is effected through the co-ordinated activation (or suppression) of genes participating in common biological pathways, which are often transcribed f...

The multitasking Promyelocytic leukemia (PML) protein was originally recognized as a tumor suppressive factor, but more recent evidence has implicated PML in tumor cell pro‐survival actions and poor patient prognosis in specific cancer settings. Here, we report that inducible PMLIV expression inhibits cell proliferation as well as self‐renewal, and...

Anti-TNF agents have been in the first line of treatment of various inflammatory diseases such as Rheumatoid Arthritis and Crohn’s Disease, with a number of different biologics being currently in use. A detailed analysis of their effect at transcriptome level has nevertheless been lacking. We herein present a concise analysis of an extended transcr...

Nucleosomes form the first level of DNA compaction and thus bear a critical role in the overall genome organization. At the same time, they modulate chromatin accessibility and, through a dynamic equilibrium with other DNA-binding proteins, may shape gene expression. A number of large-scale nucleosome positioning maps, obtained for various genomes,...

Groucho related gene 5 (GRG5) is a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. Here, we describe a previously unknown role of GRG5 in early developmental stages by analyzing its function in stem cell fate decisions. By both loss and gain of function approaches we demonstrate that ablation of G...

Background and purpose All blood cell lineages that have implicated to the pathogenesis of SLE originate from the Hematopoietic Stem Cells (HSCs). Studying HSCs may help to dissect fundamental immune aberrations in SLE and elucidate the HSC contribution to the pathogenesis of the disease. Materials and methods HSCs were isolated from either health...

Recent advances in our understanding of the three-dimensional organization of the eukaryotic nucleus have rendered the spatial distribution of genes increasingly relevant. In a recent work (Tsochatzidou et al., Nucleic Acids Res 45:5818–5828, 2017), we proposed the existence of a functional compartmentalization of the yeast genome according to whic...

Cellular DNA topoisomerases (topo I and topo II) are highly conserved enzymes that regulate the topology of DNA during normal genome transactions, such as DNA transcription and replication. In budding yeast, topo I is dispensable whereas topo II is essential, suggesting fundamental and exclusive roles for topo II, which might include the functions...

Objective: Aberrant activation of synovial fibroblasts (SFs) is a key determinant in the pathogenesis of rheumatoid arthritis (RA). We aimed to produce a map of gene expression and epigenetic changes occurring in this cell type during disease progression in the human TNF-transgenic model of arthritis, and identify commonalities with human SFs. Me...

Promyelocytic leukemia protein (PML), the main constituent of PML nuclear bodies, regulates various physiological processes in different cell types. However, little is known about its functions in embryonic stem cells (ESC). Here, we report that PML contributes to ESC self-renewal maintenance by controlling cell-cycle progression and sustaining the...

The eukaryotic genome evolves under the dual constraint of maintaining coordinated gene transcription and performing effective DNA replication and cell division, the coupling of which brings about inevitable DNA topological tension. DNA supercoiling is resolved and, in some cases, even harnessed by the genome through the function of DNA topoisomera...

Background Hematopoietic Stem Cells (HSCs) give rise to all blood cell lineages, which have been implicated in the pathogenesis of Systemic Lupus Erythematosus (SLE). We reasoned that the fundamental immune aberrations in SLE –genetic or epigenetic- may be traced back to the HSC population. We are validating and functionally characterising the mole...

Background TNF was the first cytokine to be validated as a molecular target of Rheumatoid Arthritis (RA) and still remains at the first-line of therapeutic interventions with biologics. Even though widely used anti-TNF agents, such as infliximab, etanercept, adalimumab and certolizumab pegol all target the same protein, they nonetheless exhibit dif...

Background Aberrant activation of synovial fibroblasts (SFs) is a key determinant in the pathogenesis of rheumatoid arthritis (RA). We aimed to produce a systematic map of gene expression and epigenetic changes occurring in this cell type during disease progression in the human TNF-transgenic model of arthritis, as well as identify commonalities wi...

The eukaryotic genome evolves under the dual constraint of maintaining co-ordinated gene transcription and performing effective DNA replication and cell division, the coupling of which brings about inevitable DNA topological tension. DNA supercoiling is resolved and, in some cases, even harnessed by the genome through the function of DNA topoisomer...

Rheumatoid arthritis is a progressive, highly debilitating disease where early diagnosis, enabling rapid clinical intervention, would provide obvious benefits to patients, healthcare systems and society. Novel biomarkers that enable non-invasive early diagnosis of the onset and progression of the disease provide one route to achieving this goal. He...

Strand biases reflect deviations from a null expectation of DNA evolution that assumes strand-symmetric substitution rates. Here, we present strong evidence that nearest-neighbour preferences are a strand-biased feature of bacterial genomes, indicating neighbour-dependent substitution asymmetries. To detect such asymmetries we introduce an alignmen...

Background: Under both physiological and pathological conditions gene expression programs are shaped through the interplay of regulatory proteins and their gene targets, interactions between which form intricate gene regulatory networks (GRN). While the assessment of genome-wide expression for the complete set of genes at a given condition has bec...

Table S2. Highly Abundant Deregulated miRNAs and their Overlap with Previous Studies

Table S3. miRNAs Known to Be Involved in ESC Identity and their Intersection with Our Deregulated Ones

Over the past years, microRNAs (miRNAs) have emerged as crucial factors that regulate self-renewal and differentiation of embryonic stem cells (ESCs). Although much is known about their role in maintaining ESC pluripotency, the mechanisms by which they affect cell fate decisions remain poorly understood. By performing deep sequencing to profile miR...

Significance Tumor progression locus-2 (Tpl2) is a proinflammatory gene genetically associated with inflammatory bowel diseases. This study provides a mechanistic interpretation for this association showing a dominant Tpl2-mediated homeostatic mechanism protecting mice from epithelial injury-induced colitis. This function of Tpl2 is mediated specif...

DNA damage response and repair proteins are centrally involved in genome maintenance pathways. Yet, little is known about their functional role under non-DNA damage-inducing conditions. Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription facto...

Most common methods for inquiring genomic sequence composition, are based on the bag-of-words approach and thus largely ignore the original sequence structure or the relative positioning of its constituent oligonucleotides. We here present a novel methodology that takes into account both word representation and relative positioning at various lengt...

Background and objective: Animal models are essential for development of new therapeutics but targeted therapies with biologics reveal differences in responsiveness suggesting substantial differences in the molecular pathomechanisms of human and murine arthritis. To characterize such differences, we investigated transcriptomes to develop bioinforma...

Background and objective: Animal models are essential for development of new therapeutics to test their effectiveness and to control for side effects. Targeted therapies with biologics reveal differences in responsiveness and suggest substantial differences in the molecular pathomechanisms of human as well as murine arthritis. In order to character...

Eukaryotic topoisomerase II (topo II) is the essential decatenase of newly replicated chromosomes and the main relaxase of nucleosomal DNA. Apart from these general tasks, topo II participates in more specialized functions. In mammals, topo IIα interacts with specific RNA polymerases and chromatin-remodeling complexes, whereas topo IIβ regulates de...

Animal models are essential for development of new therapeutics to test their effectiveness and to control for side effects. Targeted therapies with biologics reveal differences in responsiveness and suggest substantial differences in the molecular pathomechanisms of human as well as murine arthritis. In order to characterise such differences, we s...

Additional information on the definition and validation of consistent nucleosomes. Text containing additional information on the definition and validation of consistent nucleosomes.

Recent advances in the field of high-throughput genomics have rendered possible the performance of genome-scale studies to define the nucleosomal landscapes of eukaryote genomes. Such analyses are aimed towards providing a better understanding of the process of nucleosome positioning, for which several models have been suggested. Nevertheless, ques...

Chromatin structure influences transcription, but its role in subsequent RNA processing is unclear. Here we present analyses of high-throughput data that imply a relationship between nucleosome positioning and exon definition. First, we have found stable nucleosome occupancy within human and Caenorhabditis elegans exons that is stronger in exons wi...

Chargaff' s second parity rule (PR2) states that complementary nucleotides are met with almost equal frequencies in single stranded DNA. This is indeed the case for all bacterial and eukaryotic genomes studied, although the genomic patterns may differ among genomes in terms of local deviations. The behaviour of organellar genomes regarding the seco...

This work applies two recently formulated quantities, strongly correlated with the coding character of a sequence, as an additional "module" on GeneMark, in a three-criterial method. The difference in the statistical approaches implicated by the methods combined here, is expected to contribute to an efficient assignment of functionality to unannota...

Extensive work on n-tuplet occurrence in genomic sequences has revealed the correlation of their usage with sequence origin. Parallel to that, there exist different restrictions in the nucleotide composition of coding and noncoding sequences that may result in distinct modes of usage of n-tuplets. The relatively simple approaches described herein f...

Deviations from Chargaff's 2nd parity rule, according to which A∼T and G∼C in single stranded DNA, have been associated with replication as well as with transcription in prokaryotes. Based on observations regarding mainly the transcription-replication co-linearity in a large number of prokaryotic species, we formulate the hypothesis that the replic...

The distribution of n-tuplet frequencies is shown to strongly correlate with functionality when examining a genomic sequence in a reading-frame specific manner. The approach described herein applies a coarse-graining procedure, which is able to reveal aspects of triplet usage that are related to protein coding, while at the same time remaining spec...

The general property of asymmetry in word use in meaningful texts written in a variety of languages, motivates a quantification of the differences in the use of mutually symmetric triplets in genomic sequences. When this is done in the three reading frames, high values found for one of them are used as indication that the sequence is coding for a p...

The deviation from randomness in the distribution of nucleotides in genomic sequences is quantified and studied, using a modified standard deviation (MSD). This method implies a "per block" computation of the standard deviation of the nucleotide frequencies of occurrence, using local means (means taken in a neighborhood of each block). This quantit...