Final Report Summary - KRAB-ZNF (KRAB zinc finger gene biology in evolution and disease)
The IRSES project entitled “KRAB-ZNF KRAB zinc finger gene biology in evolution and disease” consisting of 11 work packages (WP1 to WP11) resulted in 33 deliverables and 22 milestones. Four beneficiaries from Rostock B1, Jena B2, Zürich B3 and Bonn B4 established strong research collaborations as part of the Marie Curie Actions—International Research Staff Exchange Scheme (IRSES) with the Shanghai Center of Bioinformation Technology (SCBIT), Shanghai Institute for Biological Sciences (SIBS) and the Tongji University (TUSC) studying zinc finger gene biology in evolution and disease.
The KRAB domain initially discovered as heptad repeat of leucine on December 27th, 1988, https://en.wikipedia.org/wiki/Kr%C3%BCppel_associated_box is N-terminally positioned in C2H2 zinc finger proteins. KRAB-ZNF genes are considered to be transcriptional repressors, predominantly expressed in testis and fetal brain (Fig. A Summary). Research expertise encompassed network analysis (P7 and P10), molecular structure modeling (P9), database design (P8), and deep sequencing bioinformatics (P11) with expert knowledge in KRAB-ZNF gene biology (P1), proteomics (P2), systems biology and aging (P3), interspecies brain life histories (P4), primate socio-ecology (P5), and human pathology (P6) Work packages with defined topics focused on the toponome analysis of KRAB-ZNF protein expression (Fig. 1 Summary; WP1), studying KRAB-ZNF interactions with TRIM28 (WP2), relating KRAB-ZNF gene functions to longevity (WP3), comparing brain sizes, fertility, cognitive behaviours and other aspects of life histories from birds to mammals (WP4), correlating SNPs of brain-related genes with social behaviour of e.g. primates (WP5), and on studying KRAB-ZNF protein and related target proteins thereof in human pathology (WP6). The experimental data (P1-P6) were validated in conjunction with experts in bioinformatics (P7-P11), compared to existing world-wide-knowledge (WP7), analyzed upon perturbation by small molecules (WP8), modeled upon protein interaction data (WP9), assembled in comprehensive databases (WP10), and finally studied phylogenomically (WP11). Within the funding period of 48 months, the “KRAB-ZNF” initiative achieved major contributions in elucidating KRAB-ZNF gene functions in primate evolution, ontogenesis, neural development, longevity and disease. Important results are the Web interface Utilities 2014 http://kdesrv.pzr.uni-rostock.de:8080/Utilities2014/ the Webinterface Proteinatlas (WIPA) that is online accessible under www.toponostics.org/wipa the evaluation tool to evaluate the diagnostic performance of pathologists https://131.220.23.94/online/index/. The epitope-mapping of KRAB-ZNF antibodies, the expression patterns of KRAB-ZNF proteins in human cancers and normal human tissues, a model of KRAB TRIM28 interactions, the expression of KRAB-ZNF genes from human embryonic stem cells, iPS cells, corresponding fibroblasts and neural stem cells derived thereof. The epitope-mapping of KRAB-ZNF antibodies (Fig. B Summary) was used to cross-validate the performance of the Rostock Epitope Screening Center (RESC), see manuscript Lustrek et al. 2013, entitled “Epitope predictions indicate the presence of two distinct types of epitope-antibody-reactivities determined by epitope profiling of intravenous immunoglobulins”.
The IRSES “KRAB-ZNF” initiative has been focused on deciphering KRAB-ZNF gene functions including phenomena related to brain size, cognitive behavior as well as relevant to population genetics. By making sue of appropriate IT platforms, quite diverse data sets have been assembled user-friendly web-servers that enable inhouse and open access to various data sets, see Utilities 2014 http://kdesrv.pzr.uni-rostock.de:8080/Utilities2014/. Hereto, the European Research Area is profiting on newly established collaborations that are now extended with the expectation that KRAB-ZNF genes functions can be elucidated in the near future by CRISPR-CAs9 cell models engineered based on these combined and extended IRSES effort. The research groups provided comprehensive data sets on KRAB-ZNF genes that have been expanded in primate evolution with emphasis on urang-utan genomes. The KRAB-ZNF expression seen in fetal brain is considered a key issue in conjunction with ongoing studies using induced programmed stem cells (IPSC) in order to assign distinct KRAB-ZNF to specific functionalities during cellular differentiation and organogenesis. However, KRAB zinc finger research is currently pushed by having excess to CRISPR-CAS9 knockout cells being instrumental in defining target genes thereof (Fig. C Summary). Accordingly, funding of this topic should be increased and researchers specialized in studying evolution, brain development, gene regulation, bioinformatics should be encouraged to integrate studies of KRAB-ZNF gene functions in their research. The IRSES program enabled researches for the first time to join forces from different research areas with respect to KRAB Zinc finger gene biology in a unique manner. In particular, databases have been updated and maintained ensuring a long-lasting participation of our Chinese partners to the benefit of KRAB-ZNF research specifically and sciences of health in general. The IRSES research and exchange program balanced exchange periods of experienced and of early-stage researchers leading to continuation of newly established collaboration between research groups from China and Europe as a result of the IRSES program to be maintained thereafter.
The KRAB domain initially discovered as heptad repeat of leucine on December 27th, 1988, https://en.wikipedia.org/wiki/Kr%C3%BCppel_associated_box is N-terminally positioned in C2H2 zinc finger proteins. KRAB-ZNF genes are considered to be transcriptional repressors, predominantly expressed in testis and fetal brain (Fig. A Summary). Research expertise encompassed network analysis (P7 and P10), molecular structure modeling (P9), database design (P8), and deep sequencing bioinformatics (P11) with expert knowledge in KRAB-ZNF gene biology (P1), proteomics (P2), systems biology and aging (P3), interspecies brain life histories (P4), primate socio-ecology (P5), and human pathology (P6) Work packages with defined topics focused on the toponome analysis of KRAB-ZNF protein expression (Fig. 1 Summary; WP1), studying KRAB-ZNF interactions with TRIM28 (WP2), relating KRAB-ZNF gene functions to longevity (WP3), comparing brain sizes, fertility, cognitive behaviours and other aspects of life histories from birds to mammals (WP4), correlating SNPs of brain-related genes with social behaviour of e.g. primates (WP5), and on studying KRAB-ZNF protein and related target proteins thereof in human pathology (WP6). The experimental data (P1-P6) were validated in conjunction with experts in bioinformatics (P7-P11), compared to existing world-wide-knowledge (WP7), analyzed upon perturbation by small molecules (WP8), modeled upon protein interaction data (WP9), assembled in comprehensive databases (WP10), and finally studied phylogenomically (WP11). Within the funding period of 48 months, the “KRAB-ZNF” initiative achieved major contributions in elucidating KRAB-ZNF gene functions in primate evolution, ontogenesis, neural development, longevity and disease. Important results are the Web interface Utilities 2014 http://kdesrv.pzr.uni-rostock.de:8080/Utilities2014/ the Webinterface Proteinatlas (WIPA) that is online accessible under www.toponostics.org/wipa the evaluation tool to evaluate the diagnostic performance of pathologists https://131.220.23.94/online/index/. The epitope-mapping of KRAB-ZNF antibodies, the expression patterns of KRAB-ZNF proteins in human cancers and normal human tissues, a model of KRAB TRIM28 interactions, the expression of KRAB-ZNF genes from human embryonic stem cells, iPS cells, corresponding fibroblasts and neural stem cells derived thereof. The epitope-mapping of KRAB-ZNF antibodies (Fig. B Summary) was used to cross-validate the performance of the Rostock Epitope Screening Center (RESC), see manuscript Lustrek et al. 2013, entitled “Epitope predictions indicate the presence of two distinct types of epitope-antibody-reactivities determined by epitope profiling of intravenous immunoglobulins”.
The IRSES “KRAB-ZNF” initiative has been focused on deciphering KRAB-ZNF gene functions including phenomena related to brain size, cognitive behavior as well as relevant to population genetics. By making sue of appropriate IT platforms, quite diverse data sets have been assembled user-friendly web-servers that enable inhouse and open access to various data sets, see Utilities 2014 http://kdesrv.pzr.uni-rostock.de:8080/Utilities2014/. Hereto, the European Research Area is profiting on newly established collaborations that are now extended with the expectation that KRAB-ZNF genes functions can be elucidated in the near future by CRISPR-CAs9 cell models engineered based on these combined and extended IRSES effort. The research groups provided comprehensive data sets on KRAB-ZNF genes that have been expanded in primate evolution with emphasis on urang-utan genomes. The KRAB-ZNF expression seen in fetal brain is considered a key issue in conjunction with ongoing studies using induced programmed stem cells (IPSC) in order to assign distinct KRAB-ZNF to specific functionalities during cellular differentiation and organogenesis. However, KRAB zinc finger research is currently pushed by having excess to CRISPR-CAS9 knockout cells being instrumental in defining target genes thereof (Fig. C Summary). Accordingly, funding of this topic should be increased and researchers specialized in studying evolution, brain development, gene regulation, bioinformatics should be encouraged to integrate studies of KRAB-ZNF gene functions in their research. The IRSES program enabled researches for the first time to join forces from different research areas with respect to KRAB Zinc finger gene biology in a unique manner. In particular, databases have been updated and maintained ensuring a long-lasting participation of our Chinese partners to the benefit of KRAB-ZNF research specifically and sciences of health in general. The IRSES research and exchange program balanced exchange periods of experienced and of early-stage researchers leading to continuation of newly established collaboration between research groups from China and Europe as a result of the IRSES program to be maintained thereafter.
