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249


lncRNA-screen: an interactive platform for computationally screening long non-coding RNAs in large genomics datasets

Gong, Yixiao; Huang, Hsuan-Ting; Liang, Yu; Trimarchi, Thomas; Aifantis, Iannis; Tsirigos, Aristotelis
BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a class of factors that are important for regulating development and cancer. Computational prediction of lncRNAs from ultra-deep RNA sequencing has been successful in identifying candidate lncRNAs. However, the complexity of handling and integrating different types of genomics data poses significant challenges to experimental laboratories that lack extensive genomics expertise. RESULT: To address this issue, we have developed lncRNA-screen, a comprehensive pipeline for computationally screening putative lncRNA transcripts over large multimodal datasets. The main objective of this work is to facilitate the computational discovery of lncRNA candidates to be further examined by functional experiments. lncRNA-screen provides a fully automated easy-to-run pipeline which performs data download, RNA-seq alignment, assembly, quality assessment, transcript filtration, novel lncRNA identification, coding potential estimation, expression level quantification, histone mark enrichment profile integration, differential expression analysis, annotation with other type of segmented data (CNVs, SNPs, Hi-C, etc.) and visualization. Importantly, lncRNA-screen generates an interactive report summarizing all interesting lncRNA features including genome browser snapshots and lncRNA-mRNA interactions based on Hi-C data. CONCLUSION: lncRNA-screen provides a comprehensive solution for lncRNA discovery and an intuitive interactive report for identifying promising lncRNA candidates. lncRNA-screen is available as open-source software on GitHub.
PMCID:5458484
PMID: 28583068
ISSN: 1471-2164
CID: 2590412

RNA-binding proteins, the guardians of the marginal zone

Thandapani, Palaniraja; Aranda-Orgilles, Beatriz; Aifantis, Iannis
PMID: 28518167
ISSN: 1529-2916
CID: 2562292

BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

Valls, Ester; Lobry, Camille; Geng, Huimin; Wang, Ling; Cardenas, Mariano; Rivas, Martin; Cerchietti, Leandro; Oh, Philmo; Yang, Shao Ning; Oswald, Erin; Graham, Camille W; Jiang, Yanwen; Hatzi, Katerina; Agirre, Xabier; Perkey, Eric; Li, Zhuoning; Tam, Wayne; Bhatt, Kamala; Leonard, John P; Zweidler-McKay, Patrick A; Maillard, Ivan; Elemento, Olivier; Ci, Weimin; Aifantis, Iannis; Melnick, Ari
Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and Notch pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably BCL6 up-regulation is associated with repression of Notch2 and its target genes in primary human and murine germinal center cells. Repression of Notch2 is an essential function of BCL6 in FL and GC B-cells since inducible expression of Notch2 abrogated GC formation in mice and kills FL cells. Indeed BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo. These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2.
PMCID:5413414
PMID: 28232365
ISSN: 2159-8290
CID: 2460312

Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

Pan, Feng; Wingo, Thomas S; Zhao, Zhigang; Gao, Rui; Makishima, Hideki; Qu, Guangbo; Lin, Li; Yu, Miao; Ortega, Janice R; Wang, Jiapeng; Nazha, Aziz; Chen, Li; Yao, Bing; Liu, Can; Chen, Shi; Weeks, Ophelia; Ni, Hongyu; Phillips, Brittany Lynn; Huang, Suming; Wang, Jianlong; He, Chuan; Li, Guo-Min; Radivoyevitch, Tomas; Aifantis, Iannis; Maciejewski, Jaroslaw P; Yang, Feng-Chun; Jin, Peng; Xu, Mingjiang
TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2-/- tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2-/- Lin-c-Kit+ cells shows higher mutation frequencies in Tet2-/- cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis.
PMCID:5414116
PMID: 28440315
ISSN: 2041-1723
CID: 2543782

Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Witkowski, Matthew T; Hu, Yifang; Roberts, Kathryn G; Boer, Judith M; McKenzie, Mark D; Liu, Grace J; Le Grice, Oliver D; Tremblay, Cedric S; Ghisi, Margherita; Willson, Tracy A; Horstmann, Martin A; Aifantis, Iannis; Cimmino, Luisa; Frietze, Seth; den Boer, Monique L; Mullighan, Charles G; Smyth, Gordon K; Dickins, Ross A
Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.
PMCID:5339666
PMID: 28190000
ISSN: 1540-9538
CID: 2449012

Beating the Clock in T-Cell Acute Lymphoblastic Leukemia

Carroll, William L; Aifantis, Iannis; Raetz, Elizabeth A
CDK4/6 inhibition was synergistic with dexmethasome and everolimus but antagonistic with conventional chemotherapy in T-cell acute lymphoblastic leukemia (T-ALL) pre-clinical models. Cyclin dependent kinase inhibition in combination with glucocorticoids and mTOR inhibition offers a unique therapeutic opportunity in T-ALL.
PMID: 28007775
ISSN: 1078-0432
CID: 2374552

Alternative roles for oxidized mCs and TETs

Cimmino, Luisa; Aifantis, Iannis
Ten-eleven-translocation (TET) proteins oxidize 5-methylcytosine (5mC) to form stable or transient modifications (oxi-mCs) in the mammalian genome. Genome-wide mapping and protein interaction studies have shown that 5mC and oxi-mCs have unique distribution patterns and alternative roles in gene expression. In addition, oxi-mCs may interact with specific chromatin regulators, transcription factors and DNA repair proteins to maintain genomic integrity or alter DNA replication and transcriptional elongation rates. In this review we will discuss recent advances in our understanding of how TETs and 5hmC exert their epigenetic function as tumor suppressors by playing alternative roles in transcriptional regulation and genomic stability.
PMCID:5446793
PMID: 27939598
ISSN: 1879-0380
CID: 2363242

HiC-bench: comprehensive and reproducible Hi-C data analysis designed for parameter exploration and benchmarking

Lazaris, Charalampos; Kelly, Stephen; Ntziachristos, Panagiotis; Aifantis, Iannis; Tsirigos, Aristotelis
BACKGROUND: Chromatin conformation capture techniques have evolved rapidly over the last few years and have provided new insights into genome organization at an unprecedented resolution. Analysis of Hi-C data is complex and computationally intensive involving multiple tasks and requiring robust quality assessment. This has led to the development of several tools and methods for processing Hi-C data. However, most of the existing tools do not cover all aspects of the analysis and only offer few quality assessment options. Additionally, availability of a multitude of tools makes scientists wonder how these tools and associated parameters can be optimally used, and how potential discrepancies can be interpreted and resolved. Most importantly, investigators need to be ensured that slight changes in parameters and/or methods do not affect the conclusions of their studies. RESULTS: To address these issues (compare, explore and reproduce), we introduce HiC-bench, a configurable computational platform for comprehensive and reproducible analysis of Hi-C sequencing data. HiC-bench performs all common Hi-C analysis tasks, such as alignment, filtering, contact matrix generation and normalization, identification of topological domains, scoring and annotation of specific interactions using both published tools and our own. We have also embedded various tasks that perform quality assessment and visualization. HiC-bench is implemented as a data flow platform with an emphasis on analysis reproducibility. Additionally, the user can readily perform parameter exploration and comparison of different tools in a combinatorial manner that takes into account all desired parameter settings in each pipeline task. This unique feature facilitates the design and execution of complex benchmark studies that may involve combinations of multiple tool/parameter choices in each step of the analysis. To demonstrate the usefulness of our platform, we performed a comprehensive benchmark of existing and new TAD callers exploring different matrix correction methods, parameter settings and sequencing depths. Users can extend our pipeline by adding more tools as they become available. CONCLUSIONS: HiC-bench consists an easy-to-use and extensible platform for comprehensive analysis of Hi-C datasets. We expect that it will facilitate current analyses and help scientists formulate and test new hypotheses in the field of three-dimensional genome organization.
PMCID:5217551
PMID: 28056762
ISSN: 1471-2164
CID: 2386412

FBXW7 inactivation in a BrafV600E -driven mouse model leads to melanoma development [Letter]

Aydin, Iraz T; Abbate, Franco; Rajan, Geena Susan; Badal, Brateil; Aifantis, Iannis; Desman, Garrett; Celebi, Julide Tok
PMCID:5668175
PMID: 28581198
ISSN: 1755-148x
CID: 5181262

Opposing functions of H2BK120 ubiquitylation and H3K79 methylation in the regulation of pluripotency by the Paf1 complex

Strikoudis, Alexandros; Lazaris, Charalampos; Ntziachristos, Panagiotis; Tsirigos, Aristotelis; Aifantis, Iannis
Maintenance of stem cell plasticity is determined by the ability to balance opposing forces that control gene expression. Regulation of transcriptional networks, signaling cues and chromatin-modifying mechanisms constitute crucial determinants of tissue equilibrium. Histone modifications can affect chromatin compaction, therefore co-transcriptional events that influence their deposition determine the propensities towards quiescence, self-renewal, or cell specification. The Paf1 complex (Paf1C) is a critical regulator of RNA PolII elongation that controls gene expression and deposition of histone modifications, however few studies have focused on its role affecting stem cell fate decisions. Here we delineate the functions of Paf1C in pluripotency and characterize its impact in deposition of H2B ubiquitylation (H2BK120-ub) and H3K79 methylation (H3K79me), two fundamental histone marks that shape transcriptional regulation. We identify that H2BK120-ub is increased in the absence of Paf1C on its embryonic stem cell targets, in sharp contrast to H3K79me, suggesting opposite functions in the maintenance of self-renewal. Furthermore, we found that core pluripotency genes are characterized by a dual gain of H2BK120-ub and loss of H3K79me on their gene bodies. Our findings elucidate molecular mechanisms of cellular adaptation and reveal novel functions of Paf1C in the regulation of the self-renewal network.
PMCID:5788434
PMID: 28272987
ISSN: 1551-4005
CID: 2477122