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  1. Article ; Online: seqgra: principled selection of neural network architectures for genomics prediction tasks.

    Krismer, Konstantin / Hammelman, Jennifer / Gifford, David K

    Bioinformatics (Oxford, England)

    2022  Volume 38, Issue 9, Page(s) 2381–2388

    Abstract: Motivation: Sequence models based on deep neural networks have achieved state-of-the-art performance on regulatory genomics prediction tasks, such as chromatin accessibility and transcription factor binding. But despite their high accuracy, their ... ...

    Abstract Motivation: Sequence models based on deep neural networks have achieved state-of-the-art performance on regulatory genomics prediction tasks, such as chromatin accessibility and transcription factor binding. But despite their high accuracy, their contributions to a mechanistic understanding of the biology of regulatory elements is often hindered by the complexity of the predictive model and thus poor interpretability of its decision boundaries. To address this, we introduce seqgra, a deep learning pipeline that incorporates the rule-based simulation of biological sequence data and the training and evaluation of models, whose decision boundaries mirror the rules from the simulation process.
    Results: We show that seqgra can be used to (i) generate data under the assumption of a hypothesized model of genome regulation, (ii) identify neural network architectures capable of recovering the rules of said model and (iii) analyze a model's predictive performance as a function of training set size and the complexity of the rules behind the simulated data.
    Availability and implementation: The source code of the seqgra package is hosted on GitHub (https://github.com/gifford-lab/seqgra). seqgra is a pip-installable Python package. Extensive documentation can be found at https://kkrismer.github.io/seqgra.
    Supplementary information: Supplementary data are available at Bioinformatics online.
    MeSH term(s) Genomics ; Neural Networks, Computer ; Software ; Chromatin ; Regulatory Sequences, Nucleic Acid
    Chemical Substances Chromatin
    Language English
    Publishing date 2022-02-19
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btac101
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  2. Article ; Online: spatzie: an R package for identifying significant transcription factor motif co-enrichment from enhancer-promoter interactions.

    Hammelman, Jennifer / Krismer, Konstantin / Gifford, David K

    Nucleic acids research

    2022  Volume 50, Issue 9, Page(s) e52

    Abstract: Genomic interactions provide important context to our understanding of the state of the genome. One question is whether specific transcription factor interactions give rise to genome organization. We introduce spatzie, an R package and a website that ... ...

    Abstract Genomic interactions provide important context to our understanding of the state of the genome. One question is whether specific transcription factor interactions give rise to genome organization. We introduce spatzie, an R package and a website that implements statistical tests for significant transcription factor motif cooperativity between enhancer-promoter interactions. We conducted controlled experiments under realistic simulated data from ChIP-seq to confirm spatzie is capable of discovering co-enriched motif interactions even in noisy conditions. We then use spatzie to investigate cell type specific transcription factor cooperativity within recent human ChIA-PET enhancer-promoter interaction data. The method is available online at https://spatzie.mit.edu.
    MeSH term(s) Chromatin Immunoprecipitation Sequencing ; Enhancer Elements, Genetic ; Genome ; Genomics ; Humans ; Promoter Regions, Genetic ; Software ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2022-01-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkac036
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  3. Article ; Online: IDR2D identifies reproducible genomic interactions.

    Krismer, Konstantin / Guo, Yuchun / Gifford, David K

    Nucleic acids research

    2020  Volume 48, Issue 6, Page(s) e31

    Abstract: Chromatin interaction data from protocols such as ChIA-PET, HiChIP and Hi-C provide valuable insights into genome organization and gene regulation, but can include spurious interactions that do not reflect underlying genome biology. We introduce an ... ...

    Abstract Chromatin interaction data from protocols such as ChIA-PET, HiChIP and Hi-C provide valuable insights into genome organization and gene regulation, but can include spurious interactions that do not reflect underlying genome biology. We introduce an extension of the Irreproducible Discovery Rate (IDR) method called IDR2D that identifies replicable interactions shared by chromatin interaction experiments. IDR2D provides a principled set of interactions and eliminates artifacts from single experiments. The method is available as a Bioconductor package for the R community, as well as an online service at https://idr2d.mit.edu.
    MeSH term(s) Chromatin/metabolism ; Chromatin Immunoprecipitation ; Chromosomes/genetics ; Genome ; Genomics/methods ; Reproducibility of Results ; Software
    Chemical Substances Chromatin
    Language English
    Publishing date 2020-02-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkaa030
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  4. Article ; Online: Identification of determinants of differential chromatin accessibility through a massively parallel genome-integrated reporter assay.

    Hammelman, Jennifer / Krismer, Konstantin / Banerjee, Budhaditya / Gifford, David K / Sherwood, Richard I

    Genome research

    2020  Volume 30, Issue 10, Page(s) 1468–1480

    Abstract: A key mechanism in cellular regulation is the ability of the transcriptional machinery to physically access DNA. Transcription factors interact with DNA to alter the accessibility of chromatin, which enables changes to gene expression during development ... ...

    Abstract A key mechanism in cellular regulation is the ability of the transcriptional machinery to physically access DNA. Transcription factors interact with DNA to alter the accessibility of chromatin, which enables changes to gene expression during development or disease or as a response to environmental stimuli. However, the regulation of DNA accessibility via the recruitment of transcription factors is difficult to study in the context of the native genome because every genomic site is distinct in multiple ways. Here we introduce the multiplexed integrated accessibility assay (MIAA), an assay that measures chromatin accessibility of synthetic oligonucleotide sequence libraries integrated into a controlled genomic context with low native accessibility. We apply MIAA to measure the effects of sequence motifs on cell type-specific accessibility between mouse embryonic stem cells and embryonic stem cell-derived definitive endoderm cells, screening 7905 distinct DNA sequences. MIAA recapitulates differential accessibility patterns of 100-nt sequences derived from natively differential genomic regions, identifying E-box motifs common to epithelial-mesenchymal transition driver transcription factors in stem cell-specific accessible regions that become repressed in endoderm. We show that a single binding motif for a key regulatory transcription factor is sufficient to open chromatin, and classify sets of stem cell-specific, endoderm-specific, and shared accessibility-modifying transcription factor motifs. We also show that overexpression of two definitive endoderm transcription factors,
    MeSH term(s) Animals ; Base Composition ; Chromatin/metabolism ; DNA/chemistry ; DNA/metabolism ; Embryonic Stem Cells/metabolism ; Endoderm/metabolism ; Genomics/methods ; Mice ; Nucleotide Motifs ; Oligonucleotides ; Regulatory Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Transcription Factors/metabolism
    Chemical Substances Chromatin ; Oligonucleotides ; Transcription Factors ; DNA (9007-49-2)
    Language English
    Publishing date 2020-09-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.263228.120
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  5. Article ; Online: High resolution discovery of chromatin interactions.

    Guo, Yuchun / Krismer, Konstantin / Closser, Michael / Wichterle, Hynek / Gifford, David K

    Nucleic acids research

    2019  Volume 47, Issue 6, Page(s) e35

    Abstract: Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) is a method for the genome-wide de novo discovery of chromatin interactions. Existing computational methods typically fail to detect weak or dynamic interactions because they use a ... ...

    Abstract Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) is a method for the genome-wide de novo discovery of chromatin interactions. Existing computational methods typically fail to detect weak or dynamic interactions because they use a peak-calling step that ignores paired-end linkage information. We have developed a novel computational method called Chromatin Interaction Discovery (CID) to overcome this limitation with an unbiased clustering approach for interaction discovery. CID outperforms existing chromatin interaction detection methods with improved sensitivity, replicate consistency, and concordance with other chromatin interaction datasets. In addition, CID also outperforms other methods in discovering chromatin interactions from HiChIP data. We expect that the CID method will be valuable in characterizing 3D chromatin interactions and in understanding the functional consequences of disease-associated distal genetic variations.
    MeSH term(s) Algorithms ; Chromatin/chemistry ; Chromatin/metabolism ; Chromatin Immunoprecipitation/methods ; Computational Biology/methods ; DNA-Binding Proteins/analysis ; DNA-Binding Proteins/metabolism ; Datasets as Topic ; Expressed Sequence Tags ; Humans ; Protein Binding ; Sequence Analysis, DNA/methods
    Chemical Substances Chromatin ; DNA-Binding Proteins
    Language English
    Publishing date 2019-04-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkz051
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  6. Article: Approach to machine learning for extraction of real-world data variables from electronic health records.

    Adamson, Blythe / Waskom, Michael / Blarre, Auriane / Kelly, Jonathan / Krismer, Konstantin / Nemeth, Sheila / Gippetti, James / Ritten, John / Harrison, Katherine / Ho, George / Linzmayer, Robin / Bansal, Tarun / Wilkinson, Samuel / Amster, Guy / Estola, Evan / Benedum, Corey M / Fidyk, Erin / Estévez, Melissa / Shapiro, Will /
    Cohen, Aaron B

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1180962

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2023-09-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1180962
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  7. Article ; Online: Transite: A Computational Motif-Based Analysis Platform That Identifies RNA-Binding Proteins Modulating Changes in Gene Expression.

    Krismer, Konstantin / Bird, Molly A / Varmeh, Shohreh / Handly, Erika D / Gattinger, Anna / Bernwinkler, Thomas / Anderson, Daniel A / Heinzel, Andreas / Joughin, Brian A / Kong, Yi Wen / Cannell, Ian G / Yaffe, Michael B

    Cell reports

    2020  Volume 32, Issue 8, Page(s) 108064

    Abstract: RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. Stimulus-induced alterations in RBP function contribute to global changes in gene expression, but identifying ... ...

    Abstract RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. Stimulus-induced alterations in RBP function contribute to global changes in gene expression, but identifying which RBPs are responsible for the observed changes remains an unmet need. Here, we present Transite, a computational approach that systematically infers RBPs influencing gene expression through changes in RNA stability and degradation. As a proof of principle, we apply Transite to RNA expression data from human patients with non-small-cell lung cancer whose tumors were sampled at diagnosis or after recurrence following treatment with platinum-based chemotherapy. Transite implicates known RBP regulators of the DNA damage response and identifies hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a framework for the identification of RBPs that drive cell-state transitions and adds additional value to the vast collection of publicly available gene expression datasets.
    MeSH term(s) DNA Damage/genetics ; Gene Expression/genetics ; Humans ; RNA-Binding Proteins/metabolism
    Chemical Substances RNA-Binding Proteins
    Language English
    Publishing date 2020-08-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2020.108064
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  8. Article ; Online: Acidification of Tumor at Stromal Boundaries Drives Transcriptome Alterations Associated with Aggressive Phenotypes.

    Rohani, Nazanin / Hao, Liangliang / Alexis, Maria S / Joughin, Brian A / Krismer, Konstantin / Moufarrej, Mira N / Soltis, Anthony R / Lauffenburger, Douglas A / Yaffe, Michael B / Burge, Christopher B / Bhatia, Sangeeta N / Gertler, Frank B

    Cancer research

    2019  Volume 79, Issue 8, Page(s) 1952–1966

    Abstract: Acidosis is a fundamental feature of the tumor microenvironment, which directly regulates tumor cell invasion by affecting immune cell function, clonal cell evolution, and drug resistance. Despite the important association of tumor microenvironment ... ...

    Abstract Acidosis is a fundamental feature of the tumor microenvironment, which directly regulates tumor cell invasion by affecting immune cell function, clonal cell evolution, and drug resistance. Despite the important association of tumor microenvironment acidosis with tumor cell invasion, relatively little is known regarding which areas within a tumor are acidic and how acidosis influences gene expression to promote invasion. Here, we injected a labeled pH-responsive peptide to mark acidic regions within tumors. Surprisingly, acidic regions were not restricted to hypoxic areas and overlapped with highly proliferative, invasive regions at the tumor-stroma interface, which were marked by increased expression of matrix metalloproteinases and degradation of the basement membrane. RNA-seq analysis of cells exposed to low pH conditions revealed a general rewiring of the transcriptome that involved RNA splicing and enriched for targets of RNA binding proteins with specificity for AU-rich motifs. Alternative splicing of Mena and CD44, which play important isoform-specific roles in metastasis and drug resistance, respectively, was sensitive to histone acetylation status. Strikingly, this program of alternative splicing was reversed
    MeSH term(s) Acids/adverse effects ; Alternative Splicing ; Animals ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/chemically induced ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hyaluronan Receptors/genetics ; Hyaluronan Receptors/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Transcriptome/drug effects ; Tumor Cells, Cultured ; Tumor Microenvironment/drug effects ; Xenograft Model Antitumor Assays
    Chemical Substances Acids ; Biomarkers, Tumor ; CD44 protein, human ; Enah protein, human ; Hyaluronan Receptors ; Microfilament Proteins
    Language English
    Publishing date 2019-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-18-1604
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  9. Article ; Online: A Multivariate Computational Method to Analyze High-Content RNAi Screening Data.

    Rameseder, Jonathan / Krismer, Konstantin / Dayma, Yogesh / Ehrenberger, Tobias / Hwang, Mun Kyung / Airoldi, Edoardo M / Floyd, Scott R / Yaffe, Michael B

    Journal of biomolecular screening

    2015  Volume 20, Issue 8, Page(s) 985–997

    Abstract: High-content screening (HCS) using RNA interference (RNAi) in combination with automated microscopy is a powerful investigative tool to explore complex biological processes. However, despite the plethora of data generated from these screens, little ... ...

    Abstract High-content screening (HCS) using RNA interference (RNAi) in combination with automated microscopy is a powerful investigative tool to explore complex biological processes. However, despite the plethora of data generated from these screens, little progress has been made in analyzing HC data using multivariate methods that exploit the full richness of multidimensional data. We developed a novel multivariate method for HCS, multivariate robust analysis method (M-RAM), integrating image feature selection with ranking of perturbations for hit identification, and applied this method to an HC RNAi screen to discover novel components of the DNA damage response in an osteosarcoma cell line. M-RAM automatically selects the most informative phenotypic readouts and time points to facilitate the more efficient design of follow-up experiments and enhance biological understanding. Our method outperforms univariate hit identification and identifies relevant genes that these approaches would have missed. We found that statistical cell-to-cell variation in phenotypic responses is an important predictor of hits in RNAi-directed image-based screens. Genes that we identified as modulators of DNA damage signaling in U2OS cells include B-Raf, a cancer driver gene in multiple tumor types, whose role in DNA damage signaling we confirm experimentally, and multiple subunits of protein kinase A.
    MeSH term(s) Algorithms ; Animals ; Cell Line ; Computer Simulation ; DNA Damage ; Gene Knockdown Techniques ; High-Throughput Screening Assays ; Humans ; Models, Biological ; Phenotype ; Proto-Oncogene Proteins B-raf/genetics ; RNA Interference ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics
    Chemical Substances RNA, Messenger ; RNA, Small Interfering ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2015-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1433680-7
    ISSN 1552-454X ; 1087-0571
    ISSN (online) 1552-454X
    ISSN 1087-0571
    DOI 10.1177/1087057115583037
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  10. Article ; Online: Qualifying high-throughput immune repertoire sequencing.

    Niklas, Norbert / Pröll, Johannes / Weinberger, Johannes / Zopf, Agnes / Wiesinger, Karin / Krismer, Konstantin / Bettelheim, Peter / Gabriel, Christian

    Cellular immunology

    2014  Volume 288, Issue 1-2, Page(s) 31–38

    Abstract: Diversity of B and T cell receptors, achieved by gene recombination and somatic hypermutation, allows the immune system for recognition and targeted reaction against various threats. Next-generation sequencing for assessment of a cell's gene composition ... ...

    Abstract Diversity of B and T cell receptors, achieved by gene recombination and somatic hypermutation, allows the immune system for recognition and targeted reaction against various threats. Next-generation sequencing for assessment of a cell's gene composition and variation makes deep analysis of one individual's immune spectrum feasible. An easy to apply but detailed analysis and visualization strategy is necessary to process all sequences generated. We performed sequencing utilizing the 454 system for CLL and control samples, utilized the IMGT database and applied the presented analysis tools. With the applied protocol, malignant clones are found and characterized, mutational status compared to germline identity is elaborated in detail showing that the CLL mutation status is not as monoclonal as generally thought. On the other hand, this strategy is not solely applicable to the 454 sequencing system but can easily be transferred to any other next-generation sequencing platform.
    MeSH term(s) Base Sequence ; Case-Control Studies ; Clone Cells ; Genome, Human ; Germ-Line Mutation ; High-Throughput Nucleotide Sequencing/standards ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Molecular Sequence Data ; Phylogeny ; Receptors, Antigen, B-Cell/classification ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, B-Cell/immunology ; Receptors, Antigen, T-Cell/classification ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; Sequence Alignment ; Sequence Homology, Nucleic Acid
    Chemical Substances Receptors, Antigen, B-Cell ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2014-03
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 80094-6
    ISSN 1090-2163 ; 0008-8749
    ISSN (online) 1090-2163
    ISSN 0008-8749
    DOI 10.1016/j.cellimm.2014.02.001
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