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  1. Article: Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia.

    Duński, Eryk / Pękowska, Aleksandra

    Frontiers in genetics

    2022  Volume 13, Page(s) 1009390

    Abstract: The unique qualities of the human brain are a product of a complex evolutionary process. Evolution, famously described by François Jacob as a "tinkerer," builds upon existing genetic elements by modifying and repurposing them for new functions. Genetic ... ...

    Abstract The unique qualities of the human brain are a product of a complex evolutionary process. Evolution, famously described by François Jacob as a "tinkerer," builds upon existing genetic elements by modifying and repurposing them for new functions. Genetic changes in DNA may lead to the emergence of new genes or cause altered gene expression patterns. Both gene and regulatory element mutations may lead to new functions. Yet, this process may lead to side-effects. An evolutionary trade-off occurs when an otherwise beneficial change, which is important for evolutionary success and is under strong positive selection, concurrently results in a detrimental change in another trait. Pleiotropy occurs when a gene affects multiple traits. Antagonistic pleiotropy is a phenomenon whereby a genetic variant leads to an increase in fitness at one life-stage or in a specific environment, but simultaneously decreases fitness in another respect. Therefore, it is conceivable that the molecular underpinnings of evolution of highly complex traits, including brain size or cognitive ability, under certain conditions could result in deleterious effects, which would increase the susceptibility to psychiatric or neurodevelopmental diseases. Here, we discuss possible trade-offs and antagonistic pleiotropies between evolutionary change in a gene sequence, dosage or activity and the susceptibility of individuals to autism spectrum disorders and schizophrenia. We present current knowledge about genes and alterations in gene regulatory landscapes, which have likely played a role in establishing human-specific traits and have been implicated in those diseases.
    Language English
    Publishing date 2022-11-21
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2022.1009390
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: CTCF shapes chromatin structure and gene expression in health and disease.

    Dehingia, Bondita / Milewska, Małgorzata / Janowski, Marcin / Pękowska, Aleksandra

    EMBO reports

    2022  Volume 23, Issue 9, Page(s) e55146

    Abstract: CCCTC-binding factor (CTCF) is an eleven zinc finger (ZF), multivalent transcriptional regulator, that recognizes numerous motifs thanks to the deployment of distinct combinations of its ZFs. The great majority of the ~50,000 genomic locations bound by ... ...

    Abstract CCCTC-binding factor (CTCF) is an eleven zinc finger (ZF), multivalent transcriptional regulator, that recognizes numerous motifs thanks to the deployment of distinct combinations of its ZFs. The great majority of the ~50,000 genomic locations bound by the CTCF protein in a given cell type is intergenic, and a fraction of these sites overlaps with transcriptional enhancers. Furthermore, a proportion of the regions bound by CTCF intersect genes and promoters. This suggests multiple ways in which CTCF may impact gene expression. At promoters, CTCF can directly affect transcription. At more distal sites, CTCF may orchestrate interactions between regulatory elements and help separate eu- and heterochromatic areas in the genome, exerting a chromatin barrier function. In this review, we outline how CTCF contributes to the regulation of the three-dimensional structure of chromatin and the formation of chromatin domains. We discuss how CTCF binding and architectural functions are regulated. We examine the literature implicating CTCF in controlling gene expression in development and disease both by acting as an insulator and a factor facilitating regulatory elements to efficiently interact with each other in the nuclear space.
    MeSH term(s) Binding Sites ; CCCTC-Binding Factor/genetics ; CCCTC-Binding Factor/metabolism ; Chromatin/genetics ; Enhancer Elements, Genetic ; Gene Expression ; Promoter Regions, Genetic ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
    Chemical Substances CCCTC-Binding Factor ; Chromatin ; Repressor Proteins
    Language English
    Publishing date 2022-08-22
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.15252/embr.202255146
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Evolution of neuroglia.

    Verkhratsky, Alexei / Arranz, Amaia M / Ciuba, Katarzyna / Pękowska, Aleksandra

    Annals of the New York Academy of Sciences

    2022  Volume 1518, Issue 1, Page(s) 120–130

    Abstract: The evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed of electrically excitable neuronal networks connected by chemical synapses and nonexcitable ... ...

    Abstract The evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed of electrically excitable neuronal networks connected by chemical synapses and nonexcitable glial cells that provide for homeostasis and defense. The evolution of neuroglia began with the emergence of the centralized nervous system and proceeded through a continuous increase in their complexity. In the primate brain, especially in the brain of humans, the astrocyte lineage is exceedingly complex, with the emergence of new types of astroglial cells possibly involved in interlayer communication and integration.
    MeSH term(s) Humans ; Animals ; Neuroglia/physiology ; Astrocytes/physiology ; Neurons/physiology ; Synapses/physiology ; Brain/physiology ; Oligodendroglia/physiology
    Language English
    Publishing date 2022-10-26
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 211003-9
    ISSN 1749-6632 ; 0077-8923
    ISSN (online) 1749-6632
    ISSN 0077-8923
    DOI 10.1111/nyas.14917
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue.

    Janowski, Marcin / Milewska, Małgorzata / Zare, Peyman / Pękowska, Aleksandra

    Pharmaceuticals (Basel, Switzerland)

    2021  Volume 14, Issue 8

    Abstract: Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals' lives. NDs have complex etiologies but ... ...

    Abstract Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals' lives. NDs have complex etiologies but commonly feature altered gene expression and dysfunctions of the essential chromatin-modifying factors. Hence, compounds that target DNA and histone modification pathways, the so-called epidrugs, constitute promising tools to treat NDs. Yet, targeting the entire epigenome might reveal insufficient to modify a chosen gene expression or even unnecessary and detrimental to the patients' health. New technologies hold a promise to expand the clinical toolkit in the fight against NDs. (Epi)genome engineering using designer nucleases, including CRISPR-Cas9 and TALENs, can potentially help restore the correct gene expression patterns by targeting a defined gene or pathway, both genetically and epigenetically, with minimal off-target activity. Here, we review the implication of epigenetic machinery in NDs. We outline syndromes caused by mutations in chromatin-modifying enzymes and discuss the functional consequences of mutations in regulatory DNA in NDs. We review the approaches that allow modifying the (epi)genome, including tools based on TALENs and CRISPR-Cas9 technologies, and we highlight how these new strategies could potentially change clinical practices in the treatment of NDs.
    Language English
    Publishing date 2021-08-04
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph14080765
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification.

    Liu, Chunhong / Nagashima, Hiroyuki / Fernando, Nilisha / Bass, Victor / Gopalakrishnan, Jaanam / Signorella, Sadie / Montgomery, Will / Lim, Ai Ing / Harrison, Oliver / Reich, Lauren / Yao, Chen / Sun, Hong-Wei / Brooks, Stephen R / Jiang, Kan / Nagarajan, Vijayaraj / Zhao, Yongbing / Jung, Seolkyoung / Phillips, Rachael / Mikami, Yohei /
    Lareau, Caleb A / Kanno, Yuka / Jankovic, Dragana / Aryee, Martin J / Pękowska, Aleksandra / Belkaid, Yasmine / O'Shea, John / Shih, Han-Yu

    Immunity

    2024  Volume 57, Issue 5, Page(s) 1005–1018.e7

    Abstract: Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the ... ...

    Abstract Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.
    MeSH term(s) Animals ; CCCTC-Binding Factor/metabolism ; CCCTC-Binding Factor/genetics ; Th1 Cells/immunology ; Mice ; Cell Differentiation/immunology ; Interferon-gamma/metabolism ; Binding Sites ; Interleukins/metabolism ; Interleukins/genetics ; Interleukin-22 ; Enhancer Elements, Genetic/genetics ; Mice, Inbred C57BL ; Chromatin/metabolism ; Toxoplasmosis/immunology ; Toxoplasmosis/parasitology ; Toxoplasmosis/genetics ; Gene Expression Regulation ; Toxoplasma/immunology ; Cytokines/metabolism ; Cell Lineage ; Th17 Cells/immunology
    Language English
    Publishing date 2024-05-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2024.04.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: A unique H3K4me2 profile marks tissue-specific gene regulation.

    Pekowska, Aleksandra / Benoukraf, Touati / Ferrier, Pierre / Spicuglia, Salvatore

    Genome research

    2010  Volume 20, Issue 11, Page(s) 1493–1502

    Abstract: Characterization of the epigenetic landscape fundamentally contributes toward deciphering the regulatory mechanisms that govern gene expression. However, despite an increasing flow of newly generated data, no clear pattern of chromatin modifications has ... ...

    Abstract Characterization of the epigenetic landscape fundamentally contributes toward deciphering the regulatory mechanisms that govern gene expression. However, despite an increasing flow of newly generated data, no clear pattern of chromatin modifications has so far been linked to specific modes of transcriptional regulation. Here, we used high-throughput genomic data from CD4(+) T lymphocytes to provide a comprehensive analysis of histone H3 lysine 4 dimethylation (H3K4me2) enrichment in genomic regions surrounding transcriptional start sites (TSSs). We discovered that a subgroup of genes linked to T cell functions displayed high levels of H3K4me2 within their gene body, in sharp contrast to the TSS-centered profile typical of housekeeping genes. Analysis of additional chromatin modifications and DNase I hypersensitive sites (DHSS) revealed a combinatorial chromatin signature characteristic of this subgroup. We propose that this epigenetic feature reflects the activity of an as yet unrecognized, intragenic cis-regulatory platform dedicated to refining tissue-specificity in gene expression.
    MeSH term(s) Animals ; CD4-Positive T-Lymphocytes/metabolism ; Cells, Cultured ; Chromatin Assembly and Disassembly/genetics ; Chromatin Immunoprecipitation/methods ; Cluster Analysis ; Female ; Gene Expression Regulation ; High-Throughput Nucleotide Sequencing/methods ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/genetics ; Histones/metabolism ; Humans ; Lysine/metabolism ; Male ; Metabolome ; Mice ; Organ Specificity/genetics ; Regulatory Sequences, Nucleic Acid/genetics
    Chemical Substances Histones ; Histone Methyltransferases (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2010-09-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Validation Study
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.109389.110
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Epigenetic regulation of antigen receptor gene rearrangement.

    Spicuglia, Salvatore / Zacarias-Cabeza, Joaquin / Pekowska, Aleksandra / Ferrier, Pierre

    F1000 biology reports

    2010  Volume 2

    Abstract: V(D)J recombination assembles antigen-specific immunoglobulin and T-cell receptor variable region genes from germline V, D, and J segments during lymphocyte development. Regulation of this site-specific DNA rearrangement process occurs with respect to ... ...

    Abstract V(D)J recombination assembles antigen-specific immunoglobulin and T-cell receptor variable region genes from germline V, D, and J segments during lymphocyte development. Regulation of this site-specific DNA rearrangement process occurs with respect to the cell type and stage of differentiation, order of locus recombination, and allele usage. Many of these controls are mediated via the modulation of gene accessibility to the V(D)J recombinase. Here, we summarise recent advances regarding the impact of nuclear organisation and epigenetic-based mechanisms on the regulation of V(D)J recombination.
    Language English
    Publishing date 2010-03-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 2486077-3
    ISSN 1757-594X ; 1757-594X
    ISSN (online) 1757-594X
    ISSN 1757-594X
    DOI 10.3410/B2-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Epigenetic control of Tcrb gene rearrangement.

    Spicuglia, Salvatore / Pekowska, Aleksandra / Zacarias-Cabeza, Joaquin / Ferrier, Pierre

    Seminars in immunology

    2010  Volume 22, Issue 6, Page(s) 330–336

    Abstract: V(D)J recombination assembles antigen receptor genes from germline V, D and J segments during lymphocyte development. In αβT-cells, this leads to the subsequent expression of T-cell receptor (TCR) β and α chains. Generally, V(D)J recombination is closely ...

    Abstract V(D)J recombination assembles antigen receptor genes from germline V, D and J segments during lymphocyte development. In αβT-cells, this leads to the subsequent expression of T-cell receptor (TCR) β and α chains. Generally, V(D)J recombination is closely controlled at various levels, including cell-type and cell-stage specificities, order of locus/gene segment recombination, and allele usage to mediate allelic exclusion. Many of these controls rely on the modulation of gene accessibility to the recombination machinery, involving not only biochemical changes in chromatin arrangement and structural modifications of chromosomal organization and positioning, but also the refined composition of the recombinase targets, the so-called recombination signal sequences. Here, we summarize current knowledge regarding the regulation of V(D)J recombination at the Tcrb gene locus, certainly one for which these various levels of control and regulatory components have been most extensively investigated.
    MeSH term(s) Alleles ; Animals ; Epigenomics ; Humans ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Recombination, Genetic ; T-Lymphocytes/metabolism
    Chemical Substances Receptors, Antigen, T-Cell, alpha-beta
    Language English
    Publishing date 2010-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1018141-6
    ISSN 1096-3618 ; 1044-5323
    ISSN (online) 1096-3618
    ISSN 1044-5323
    DOI 10.1016/j.smim.2010.07.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Assessing the efficiency and significance of Methylated DNA Immunoprecipitation (MeDIP) assays in using in vitro methylated genomic DNA

    Jia Jinsong / Pekowska Aleksandra / Jaeger Sebastien / Benoukraf Touati / Ferrier Pierre / Spicuglia Salvatore

    BMC Research Notes, Vol 3, Iss 1, p

    2010  Volume 240

    Abstract: Abstract Background DNA methylation contributes to the regulation of gene expression during development and cellular differentiation. The recently developed Methylated DNA ImmunoPrecipitation (MeDIP) assay allows a comprehensive analysis of this ... ...

    Abstract Abstract Background DNA methylation contributes to the regulation of gene expression during development and cellular differentiation. The recently developed Methylated DNA ImmunoPrecipitation (MeDIP) assay allows a comprehensive analysis of this epigenetic mark at the genomic level in normal and disease-derived cells. However, estimating the efficiency of the MeDIP technique is difficult without previous knowledge of the methylation status of a given cell population. Attempts to circumvent this problem have involved the use of in vitro methylated DNA in parallel to the investigated samples. Taking advantage of this stratagem, we sought to improve the sensitivity of the approach and to assess potential biases resulting from DNA amplification and hybridization procedures using MeDIP samples. Findings We performed MeDIP assays using in vitro methylated DNA, with or without previous DNA amplification, and hybridization to a human promoter array. We observed that CpG content at gene promoters indeed correlates strongly with the MeDIP signal obtained using in vitro methylated DNA, even when lowering significantly the amount of starting material. In analyzing MeDIP products that were subjected to whole genome amplification (WGA), we also revealed a strong bias against CpG-rich promoters during this amplification procedure, which may potentially affect the significance of the resulting data. Conclusion We illustrate the use of in vitro methylated DNA to assess the efficiency and accuracy of MeDIP procedures. We report that efficient and reproducible genome-wide data can be obtained via MeDIP experiments using relatively low amount of starting genomic DNA; and emphasize for the precaution that must be taken in data analysis when an additional DNA amplification step is required.
    Keywords Medicine ; R ; Biology (General) ; QH301-705.5 ; Science (General) ; Q1-390
    Subject code 570
    Language English
    Publishing date 2010-09-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article: Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency.

    Pękowska, Aleksandra / Klaus, Bernd / Xiang, Wanqing / Severino, Jacqueline / Daigle, Nathalie / Klein, Felix A / Oleś, Małgorzata / Casellas, Rafael / Ellenberg, Jan / Steinmetz, Lars M / Bertone, Paul / Huber, Wolfgang

    Cell systems

    2018  Volume 7, Issue 5, Page(s) 482–495.e10

    Abstract: The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that ...

    Abstract The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes.
    MeSH term(s) Animals ; CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/metabolism ; Cell Differentiation ; Chromatin/metabolism ; Chromatin/ultrastructure ; Chromosomal Proteins, Non-Histone/metabolism ; Mice ; Mouse Embryonic Stem Cells/metabolism ; Mouse Embryonic Stem Cells/physiology ; Mouse Embryonic Stem Cells/ultrastructure ; Neural Stem Cells/metabolism ; Neural Stem Cells/physiology ; Neural Stem Cells/ultrastructure ; Protein Binding ; Cohesins
    Chemical Substances CCCTC-Binding Factor ; Cell Cycle Proteins ; Chromatin ; Chromosomal Proteins, Non-Histone ; Ctcf protein, mouse
    Language English
    Publishing date 2018-11-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2854138-8
    ISSN 2405-4720 ; 2405-4712
    ISSN (online) 2405-4720
    ISSN 2405-4712
    DOI 10.1016/j.cels.2018.09.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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