Roza Berhanu Lemma

• Lemma, Roza Berhanu; Fleischer, Thomas; Martinsen, Emily; Ledsaak, Marit; Kristensen, Vessela N. & Eskeland, Ragnhild [Show all 8 contributors for this article] (2022). Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers. Epigenetics & Chromatin. ISSN 1756-8935. 15. doi: 10.1186/s13072-022-00444-9.
• Clarke, Mary L.; Lemma, Roza Berhanu; Walton, David Scott; Volpe, G; Noyvert, Boris & Gabrielsen, Odd Stokke [Show all 7 contributors for this article] (2021). MYB insufficiency disrupts proteostasis in hematopoietic stem cells leading to age-related neoplasia. BioRxiv. ISSN 0362-4331. doi: 10.1101/2021.09.04.458970.
• Castro Mondragon, Jaime Abraham; Riudavets Puig, Rafael; Rauluseviciute, Ieva; Lemma, Roza Berhanu; Turchi, Laura & Blanc-Mathieu, Romain [Show all 23 contributors for this article] (2021). JASPAR 2022: the 9th release of the open-acess database of transcription factor binding profiles. Nucleic Acids Research (NAR). ISSN 0305-1048. doi: 10.1093/nar/gkab1113. Full text in Research Archive
• Lemma, Roza Berhanu; Ledsaak, Marit; Fuglerud, Bettina Maria; Sandve, Geir Kjetil; Eskeland, Ragnhild & Gabrielsen, Odd Stokke (2021). Chromatin occupancy and target genes of the haematopoietic master transcription factor MYB. Scientific Reports. ISSN 2045-2322. 11(9008). doi: 10.1038/s41598-021-88516-w. Full text in Research Archive Show summary

  The transcription factor MYB is a master regulator in haematopoietic progenitor cells and a pioneer factor affecting differentiation and proliferation of these cells. Leukaemic transformation may be promoted by high MYB levels. Despite much accumulated molecular knowledge of MYB, we still lack a comprehensive understanding of its target genes and its chromatin action. In the present work, we performed a ChIP-seq analysis of MYB in K562 cells accompanied by detailed bioinformatics analyses. We found that MYB occupies both promoters and enhancers. Five clusters (C1–C5) were found when we classified MYB peaks according to epigenetic profiles. C1 was enriched for promoters and C2 dominated by enhancers. C2-linked genes were connected to hematopoietic specific functions and had GATA factor motifs as second in frequency. C1 had in addition to MYB-motifs a significant frequency of ETS-related motifs. Combining ChIP-seq data with RNA-seq data allowed us to identify direct MYB target genes. We also compared ChIP-seq data with digital genomic footprinting. MYB is occupying nearly a third of the super-enhancers in K562. Finally, we concluded that MYB cooperates with a subset of the other highly expressed TFs in this cell line, as expected for a master regulator

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2020). LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction. Cells. ISSN 2073-4409. 9(5), p. 1–26. doi: 10.3390/cells9051214. Full text in Research Archive Show summary

  The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show that LXRα and ChREBPα interact physically and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; the low glucose inhibitory domain (LID) of ChREBPα and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie Maria; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2019). Open the LID: LXRα regulates ChREBPα transactivity in a target gene-specific manner through an agonist-modulated LBD-LID interaction. BioRxiv. ISSN 0362-4331. doi: 10.1101/2019.12.20.869974. Show summary

  The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXRα and ChREBPα interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα, and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; ChREBPα’s low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα that was overlooked due to LXR lipogenesis-promoting function.

• Rodriguez- Castañeda, Fernando; Lemma, Roza Berhanu; Cuervo Torre, Ignacio; Bengtsen, Mads; Moen, Lisa Marie & Ledsaak, Marit [Show all 8 contributors for this article] (2018). The SUMO protease SENP1 and the chromatin remodeller CHD3 interact and jointly affect chromatin accessibility and gene expression. Journal of Biological Chemistry. ISSN 0021-9258. 293(40), p. 15439–15454. doi: 10.1074/jbc.RA118.002844. Full text in Research Archive Show summary

  The small ubiquitin-like modifier (SUMO) post-translationally modifies lysine residues of transcription factors and co-regulators and thereby contributes to an important layer of control of the activities of these transcriptional regulators. Likewise, deSUMOylation of these factors by the sentrin-specific proteases (SENPs) also plays a role in gene regulation, but whether SENPs functionally interact with other regulatory factors that control gene expression is unclear. In the present work, we focused on SENP1, specifically, on its role in activation of gene expression investigated through analysis of the SENP1 interactome, which revealed that SENP1 physically interacts with the chromatin remodeler chromodomain helicase DNA-binding protein 3 (CHD3). Using several additional methods, including GST pull-down and co-immunoprecipitation assays, we validated and mapped this interaction, and using CRISPR-Cas9–generated CHD3- and SENP1-KO cells (in the haploid HAP1 cell line), we investigated whether these two proteins are functionally linked in regulating chromatin remodeling and gene expression. Genome-wide ATAC-Seq analysis of the CHD3- and SENP1-KO cells revealed a large degree of overlap in differential chromatin openness between these two mutant cell lines. Moreover, motif analysis and comparison with ChIP-Seq profiles in K562 cells pointed to an association of CHD3 and SENP1 with CCCTC-binding factor (CTCF) and SUMOylated chromatin–associated factors. Lastly, genome-wide RNA-Seq also indicated that these two proteins co-regulate the expression of several genes. We propose that the functional link between chromatin remodeling by CHD3 and deSUMOylation by SENP1 uncovered here provides another level of control of gene expression.

• Fuglerud, Bettina Maria; Lemma, Roza Berhanu; Wanichawan, Pimthanya; Sundaram, Arvind; Eskeland, Ragnhild & Gabrielsen, Odd Stokke (2017). A c-Myb mutant causes deregulated differentiation due to impaired histone binding and abrogated pioneer factor function. Nucleic Acids Research (NAR). ISSN 0305-1048. 45(13), p. 7681–7696. doi: 10.1093/nar/gkx364. Full text in Research Archive

View all works in Cristin

• Lemma, Roza Berhanu (2022). Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers (NBD2022). Show summary

  Epigenetics marks such as chromatin and DNA modifications act as molecular stamps defining active or inactive regulatory states that are crucial for proper homeostasis and development. These marks can be recognized and read by epigenetic readers such as transcription factors (TFs), thereby influencing transcription. Among the various DNA modifications, methylation of cytosines on DNA is a prominent modification associated with gene expression regulation. Aberrant DNA methylation patterns have recurrently been linked to dysregulation of the regulatory program in cancer cells. To understand the underlying molecular mechanism driving this process, we hypothesized that aberrant methylation patterns could be regulated by the binding of specific TFs across cancer types. We combined DNA methylation arrays and gene expression data from The Cancer Genome Atlas (TCGA) with high quality TF binding sites (TFBSs) from the UniBind database (version 2018) to explore the interplay between TF binding and DNA methylation in 19 cancer types. Using these combined data, we performed emQTL (expression-methylation quantitative trait loci) analyses in each cancer type independently (See Figure 1A for short overview of the emQTL analysis workflow and Figure 1B for fraction of correlated CpGs per cancer type) and identified 13 TFs whose expression levels are correlated with local DNA methylation patterns around their binding sites in at least 2 cancer types. These 13 TFs, which we referred to as emTFs (expression methylation TFs) are mainly associated with local demethylation and are enriched for pioneer function, suggesting a specific role for these TFs in modulating chromatin structure and transcription in cancer patients. Furthermore, we confirmed that de novo methylation is precluded across cancers at CpGs lying in genomic regions enriched for TF-binding signatures previously reported in protecting DNA from de novo DNA methylation. Among our predicted emTFs, many were in agreement with other predictions including a recent back-to-back paper by Detilleux et al. We observed modulation of DNA methylation associated with TF binding at cis-regulatory regions controlling immune- and cancer-associated pathways, indicating that the emQTL signals were derived from both cancer and tumor-infiltrating cells. As a case example, we experimentally confirmed that FOXA1 knock-down is associated with higher methylation in regions bound by FOXA1 in breast cancer MCF-7 cells. Finally, we reported physical interactions between FOXA1 with TET1 and TET2 both in an in vitro setup and in vivo at physiological levels in MCF-7 cells adding further support for FOXA1 attracting TET1 and TET2 to induce local demethylation in cancer cells.

• Nederbragt, Lex; Lemma, Roza Berhanu; Belova, Tatiana; Cheneby, Jeanne; Ibrahim, Mohamed & Akdeniz, Byram Cevdet [Show all 7 contributors for this article] (2022). Oslo Bioinformatics Workshop Week 2022. Show summary

  December 7th-13th 2022 will see the very first Oslo Bioinformatics Workshop Week at the University of Oslo, Norway. This event is organised by the Student Committee of the Centre for Bioinformatics at UiO, in collaboration with the ISCB Regional Student group in Norway. These workshops are open to the scientific community in Oslo and the surrounding area.

• Kumar, Vipin; Fatima, Nazeefa; Hsieh, Ping-Han; Belova, Tatiana; Ferenc, Katalin Terezia & Rauluseviciute, Ieva [Show all 9 contributors for this article] (2022). Introducing ISCB's (International Society for Computational Biology) regional student group in Norway's (RSG-Norway's) activities to the PhD and postdoc forum at the Institute of Cancer research, Radium hospital, OUS .
• Fatima, Nazeefa; Lemma, Roza Berhanu; Rauluseviciute, Ieva; Belova, Tatiana; Kumar, Vipin & Hsieh, Ping-Han [Show all 12 contributors for this article] (2022). Developing Bioinformatics Societies in Norway and Nordic. Show summary

  With the increasing amount of biological data, the need for computational skills has become prominent. Interdisciplinary fields such as computational biology require interdisciplinary collaborations; in order to create an environment for sharing skills and experiences, opportunities for funding and training, career path advice, and research ideas. Creating such environments also help to establish an inclusive platform where students and early-career researchers in computational biology can socialise and help each other in an informal setting. Currently, this is achieved locally at department level at a university or industrial company. The social interactions between students and established scientists are, therefore, consequently limited to the geographical locations of their institutions. The Regional Study Group Norway (RSG-Norway), part of the International Society of Computational Biology (ISCB), aims to create a country-wide platform, to bring together aspiring and established bioinformaticians and to develop an active presence in the Norwegian bioinformatics community. Regional level communities such as RSG-Norway are particularly helpful for students to broaden training and career opportunities. It can also help foreign researchers and students, in settling as new arrivals, through building contacts with those who are familiar with studying and working in Norway. Finally, the study group can be a channel for students and trainees to initiate and/or realise their own ideas regarding social and professional communication with fellow bioinformaticians. RSG-Norway works together with Nordic Computational Biology (NCB), which serves as a resource and knowledge-exchange hub to bring together people from industries and academia as well as local communities such as Regional Student Groups across the Nordics. As part of the NCB, Nordic RSGs are able to build cross-border collaborations and organise open events that reach a wider audience strengthening the community's knowledge-base. The presentation for this abstract will include information on past events and initiatives by RSG-Norway and NCB, their future activities and plans, and how to get involved as a member and an advisor to help develop the computational biology community in Norway and the Nordics.

• Lemma, Roza Berhanu; Castro-Mondragon, Jaime Abraham & Mathelier, Anthony (2022). Large-scale investigation of noncoding elements associated with transcriptional deregulation involved in carcinogenesis.
• Lemma, Roza Berhanu (2022). Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers. Show summary

  Methylation of cytosines on DNA is a prominent modification associated with gene expression regulation. Aberrant DNA methylation patterns have recurrently been linked to dysregulation of the regulatory program in cancer cells. To shed light on the underlying molecular mechanism driving this process, we hypothesised that aberrant methylation patterns could be controlled by the binding of specific transcription factors (TFs) across cancer types. By combining DNA methylation arrays and gene expression data with TF binding sites (TFBSs), we explored the interplay between TF binding and DNA methylation in 19 cancer types. We performed emQTL (expression–methylation quantitative trait loci) analyses independently in each cancer type and identified 13 TFs whose expression levels are correlated with local DNA methylation patterns around their binding sites in at least 2 cancer types. The 13 TFs are mainly associated with local demethylation and are enriched for pioneer function, suggesting a specific role for these TFs in modulating chromatin structure and transcription in cancer patients. Furthermore, we confirmed that de novo methylation is precluded across cancers at CpGs lying in genomic regions enriched for TF binding signatures associated with SP1, CTCF, NRF1, GABPA, KLF9, and/or YY1. The modulation of DNA methylation associated with TF binding was observed at cis-regulatory regions controlling immune- and cancer-associated pathways, corroborating that the emQTL signals were derived from both cancer and tumor-infiltrating cells. As a case example, we experimentally confirmed that FOXA1 knock-down is associated with higher methylation in regions bound by FOXA1 in breast cancer MCF-7 cells. Finally, we reported physical interactions between FOXA1 with TET1 and TET2 both in an in vitro setup and in vivo at physiological levels in MCF-7 cells, adding further support for FOXA1 attracting TET1 and TET2 to induce local demethylation in cancer cells.

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie Maria; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2019). LXRα interacts with the glucose-sensing transcription factor ChREBPα to regulate its transcriptional activity.
• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ulven, Stine Marie; Lucas, Christin & Bindesbøll, Christian [Show all 11 contributors for this article] (2018). LXRα interacts with the glucose-sensing transcription factor ChREBPα and increases its transcriptional activity.

View all works in Cristin