Dr. Nati Ha
Dr. Nati Ha
ed.grebledieh-inu.hzb TEA ah.itan
Nati Ha, Postdoc
der Universität Heidelberg (BZH)
Im Neuenheimer Feld 328
der Universität Heidelberg (BZH)
Im Neuenheimer Feld 328
Büro: Raum 504 / Tel.: +49 6221 54-4774
Current Project: COPS
Run COPS online: COPS_online
Ha N, Polychronidou M, Lohmann I. (2012). COPS: Detecting Co-Occurrence and Spatial Arrangement of Transcription Factor Binding Motifs in Genome-Wide Datasets. 1. PLoS One. 2012;7(12):e52055.
In multi-cellular organisms, spatiotemporal activity of cis-regulatory DNA elements depends on their occupancy by different transcription factors (TFs). In recent years, genome-wide ChIP-on-Chip, ChIP-Seq and DamID assays have been extensively used to unravel the combinatorial interaction of TFs with cis-regulatory modules (CRMs) in the genome. Even though genome-wide binding profiles are increasingly becoming available for different TFs, single TF binding profiles are in most cases not sufficient for dissecting complex regulatory networks. Thus, potent computational tools detecting statistically significant and biologically relevant TF-motif co-occurrences in genome-wide datasets are essential for analyzing context-dependent transcriptional regulation. We have developed COPS (Co-Occurrence Pattern Search), a new bioinformatics tool based on a combination of association rules and Markov chain models, which detects co-occurring TF binding sites (BSs) on genomic regions of interest. COPS scans DNA sequences for frequent motif patterns using a Frequent-Pattern tree based data mining approach, which allows efficient performance of the software with respect to both data structure and implementation speed, in particular when mining large datasets. Since transcriptional gene regulation very often relies on the formation of regulatory protein complexes mediated by closely adjoining TF binding sites on CRMs, COPS additionally detects preferred short distance between co-occurring TF motifs. The performance of our software with respect to biological significance was evaluated using three published datasets containing genomic regions that are independently bound by several TFs involved in a defined biological process. In sum, COPS is a fast, efficient and user-friendly tool mining statistically and biologically significant TFBS co-occurrences and therefore allows the identification of TFs that combinatorially regulate gene expression.
Sorge S, Ha N, Polychronidou M, Friedrich J, Bezdan D, Kaspar P, Schaefer MH, Ossowski S, Henz SR, Mundorf J, Rätzer J, Papagiannouli F, Lohmann I. (2012). The cis-regulatory code of Hox function in Drosophila. EMBO J. 31(15):3323-33.
Precise gene expression is a fundamental aspect of organismal function and depends on the combinatorial interplay of transcription factors (TFs) with cis-regulatory DNA elements. While much is known about TF function in general, our understanding of their cell type-specific activities is still poor. To address how widely expressed transcriptional regulators modulate downstream gene activity with high cellular specificity, we have identified binding regions for the Hox TF Deformed (Dfd) in the Drosophila genome. Our analysis of architectural features within Hox cis-regulatory response elements (HREs) shows that HRE structure is essential for cell type-specific gene expression. We also find that Dfd and Ultrabithorax (Ubx), another Hox TF specifying different morphological traits, interact with non-overlapping regions in vivo, despite their similar DNA binding preferences. While Dfd and Ubx HREs exhibit comparable design principles, their motif compositions and motif-pair associations are distinct, explaining the highly selective interaction of these Hox proteins with the regulatory environment. Thus, our results uncover the regulatory code imprinted in Hox enhancers and elucidate the mechanisms underlying functional specificity of TFs in vivo.
Christ A, Maegele I, Ha N, Nguyen HH, Crespi MD, Maizel A. (2012). In silico identification and in vivo validation of a set of evolutionary conserved plant root-specific cis-regulatory elements. 3. Mech Dev. 2012 Apr 4. [
Marker genes are specifically expressed in a tissue, organ or time of development. Here we used a computational screen to identify marker genes of the root in Arabidopsis thaliana. We mined the existing transcriptome datasets for genes having high expression in roots while being low in all other organs under a wide range of growth conditions. We show that the root-specificity of these genes is conserved in the sister species Arabidopsis lyrata, indicating that their expression pattern is under selective pressure. We delineated the cis-regulatory elements responsible for root-specific expression and validated two third of those in planta as bona fide root-specific regulatory sequences. We identified three motifs over-represented in these sequences, which mutation resulted in alteration of root-specific expression, demonstrating that these motifs are functionally relevant. In addition, the three motifs are also over-represented in the cis-regulatory regions of the A. lyrata orthologs of our root-specific genes, and this despite an overall low degree of sequence conservation of these regions. Our results provide a resource to assess root-identity in the model genus Arabidopsis and shed light on the evolutionary history of gene regulation in plants.
Zhai Z, Ha N, Papagiannouli F, Hamacher-Brady A, Brady N, Sorge S, Bezdan D, Lohmann I. (2012). Antagonistic regulation of apoptosis and differentiation by the Cut transcription factor represents a tumor-suppressing mechanism in Drosophila. 4. PLoS Genet. 2012;8(3):e1002582.
Comment in Nat Rev Cancer. 2012 May;12(5):320.
Sancar G, Sancar C, Brügger B, Ha N, Sachsenheimer T, Gin E, Wdowik S, Lohmann I, Wieland F, Höfer T, Diernfellner A, Brunner M. (2011). A global circadian repressor controls antiphasic expression of metabolic genes in Neurospora. Mol Cell. 44(5):687-97.
AbstractCopyright © 2011 Elsevier Inc. All rights reserved.
Comment in Mol Cell. 2011 Dec 9;44(5):679-81.
Pakkanen S, Kujala PM, Ha N, Matikainen MP, Schleutker J, Tammela TL. (2011). Clinical and histopathological characteristics of familial prostate cancer in Finland. BJU Int. 109(4):557-63.
OBJECTIVE: • To describe clinical and histopathological characteristics of Finnish familial prostate cancer (PCa) through a detailed analysis of cases in families. PATIENTS AND METHODS: • In total, 202 Finnish families with 617 histopathologically confirmed PCa cases of confirmed genealogy were collected. • Complete clinical data, including age and prostate-specific antigen (PSA) at diagnosis, stage, grade and primary treatment, were gathered. The mean (range) number of affected men per family was 3 (2-8). • All the available diagnostic biopsy samples (n= 323) were collected and regraded by the same uropathologist. • A population-based cohort of 3011 hospital district Pirkanmaa PCa patients was used as a control group. RESULTS: • The mean (range) year of diagnosis of PCa was 1993 (1962-2006) and the mean (range) age at diagnosis was 68 (43-98 years). • The median (range) primary PSA level was 12.0 (0.8-11 000) ng/mL. After regrading, the Gleason score was ≤6 in 38%, 7 in 37% and ≥8 in 25% of men. • The subset of familial PCa men diagnosed after 1995 had higher PSA levels (P= 9.9 × 10(-6) ) and an earlier age of onset (P= 1.7 × 10(-6) ) than men in the control group, although there were no differences in cancer-specific survival. CONCLUSIONS: • We observed an earlier age of onset and higher PSA in familial PCa. • However, differences between sporadic and familial or hereditary PCa cannot be truly solved until genetic testing of high-risk genes in addition to family history is used to define PCa families. • We also emphasize that, when histological samples are collected over a longer study period, reanalysis of the samples by the same experienced uropathologist should be considered.
Cropp CD, Simpson CL, Wahlfors T, Ha N, George A, Jones MS, Harper U, Ponciano-Jackson D, Green TA, Tammela TL, Bailey-Wilson J, Schleutker J. (2011). Genome-wide linkage scan for prostate cancer susceptibility in Finland: evidence for a novel locus on 2q37.3 and confirmation of signal on 17q21-q22. Int J Cancer. 129(10):2400-7.
Genome-wide linkage studies have been used to localize rare and highly penetrant prostate cancer (PRCA) susceptibility genes. Linkage studies performed in different ethnic backgrounds and populations have been somewhat disparate, resulting in multiple, often irreproducible signals because of genetic heterogeneity and high sporadic background of the disease. Our first genome-wide linkage study and subsequent fine-mapping study of Finnish hereditary prostate cancer (HPC) families gave evidence of linkage to one region. Here, we conducted subsequent scans with microsatellites and SNPs in a total of 69 Finnish HPC families. GENEHUNTER-PLUS was used for parametric and nonparametric analyses. Our microsatellite genome-wide linkage study provided evidence of linkage to 17q12-q23, with a heterogeneity LOD (HLOD) score of 3.14 in a total of 54 of the 69 families. Genome-wide SNP analysis of 59 of the 69 families gave a highest HLOD score of 3.40 at 2q37.3 under a dominant high penetrance model. Analyzing all 69 families by combining microsatellite and SNP maps also yielded HLOD scores of > 3.3 in two regions (2q37.3 and 17q12-q21.3). These significant linkage peaks on chromosome 2 and 17 confirm previous linkage evidence of a locus on 17q from other populations and provide a basis for continued research into genetic factors involved in PRCA. Fine-mapping analysis of these regions is ongoing and candidate genes at linked loci are currently under analysis.
Busch W, Miotk A, Ariel FD, Zhao Z, Forner J, Daum G, Suzaki T, Schuster C, Schultheiss SJ, Leibfried A, Haubeiss S, Ha N, Chan RL, Lohmann JU. (2010). Transcriptional control of a plant stem cell niche. Dev Cell. 18(5):849-61.
AbstractCopyright 2010 Elsevier Inc. All rights reserved.
Comment in Dev Cell. 2010 May 18;18(5):696-7.