Biswajyoti Sahu

• Tiusanen, Ville; Patel, Divyeshkumar Amrubthai; Xia, Jihan; Xu, Chi; Datta, Subhamoy & Yun, Ji [Vis alle 13 forfattere av denne artikkelen] (2026). Classical enhancers couple cis-regulatory logic with transcriptional condensates and 3D genome architecture. bioRxiv - the preprint server for biology. doi: 10.64898/2026.01.23.701252. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Deciphering the regulatory logic of enhancers remains a central question in understanding cell- and tissue-specific gene expression in multicellular organisms. This is particularly pertinent at multipartite enhancer clusters such as super-enhancers, where multiple enhancers contribute to the expression of a single gene. Gene expression has been studied largely through sequence-dependent recruitment of transcription factors (TF) and co-activators, whereas 3D chromatin structure has been attributed to architectural proteins such as cohesion and CTCF 1–3 . However, the contribution of DNA sequence encoded in enhancers to shaping higher-order genome organization remains poorly understood. Here we show that classical enhancers, embedded within multipartite super-enhancer structures, act as determinant regulatory elements that initiate the gene regulatory cascade by linking DNA sequence recognition to 3D chromatin architecture. Classical enhancers are more evolutionarily conserved and display stronger regulatory activity than facilitator elements, which lack intrinsic enhancer activity but potentiate classical enhancer function. We show that classical enhancers are selectively bound by specific TFs with strong intrinsically disordered regions, such as NFE2L2 in liver cancer cells, capable of driving transcriptional condensate formation through phase separation. NFE2L2 depletion reduced enhancer activity and induced widespread chromatin reorganization, characterized by increased cohesin and CTCF occupancy at super-enhancer boundaries and beyond. This “cohesin clogging” impaired DNA loop extrusion, led to formation of smaller topologically associated domains, and weakened enhancer–promoter contacts. These findings highlight that sequence-specific TFs have multifaceted roles beyond transcriptional control, establishing a direct mechanistic link between enhancer sequence, TF binding, condensate formation, and 3D genome organization, with the regulatory logic being encoded in the DNA sequence itself.

• Koski, Yrjö; Patel, Divyesh; Koch, Natalia Kakko von; Jouhten, Paula; Aaltonen, Lauri & Palin, Kimmo [Vis alle 8 forfattere av denne artikkelen] (2025). Compound-specific DNA adduct profiling with nanopore sequencing and IonStats. bioRxiv - the preprint server for biology. doi: 10.1101/2025.10.31.685820. Fulltekst i vitenarkiv Vis sammendrag

  A bstract Covalently bound DNA adducts are mutation precursors that contribute to aging and diseases such as cancer. Accurate detection of adducts in the genome will shed light on tumorigenesis. Commonly used detection methods are unable to pinpoint the exact genomic locations of adducts. Long-read nanopore sequencing has the potential to accurately detect multiple types of DNA adducts at single-nucleotide precision. In this study, we developed a novel statistical toolkit, IonStats, to profile DNA adducts in nanopore sequencing data. With IonStats, we investigated the effects of four adduct-inducing genotoxic compounds on nanopore sequencing, and found both shared and compound-specific perturbations in base quality scores, ionic current profiles, and translocation dynamics. Notably, aristolochic acid II and melphalan treatments profoundly altered nanopore readouts and led to substantial sequence-specific read interruptions. Our study shows that nanopore sequencing can be effectively employed to detect and characterize DNA adducts, paving the way for high-resolution, high-throughput profiling of DNA damage and the exposome.

• Tuohinto, Krista; Graus, Matthew S.; Staab, Peyton; Tiusanen, Ville; Fei, Liangru & Pradhan, Susav [Vis alle 20 forfattere av denne artikkelen] (2025). Oncogenic virus hijacks SOX18 pioneer function to enhance viral persistence. bioRxiv - the preprint server for biology. doi: 10.1101/2025.06.28.662102. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Kaposi’s sarcoma herpesvirus (KSHV) establishes lifelong oncogenic infection in lymphatic endothelial cells (LECs) by ensuring episomal maintenance of its genome via the viral protein LANA. Efficient viral genome maintenance typically involves host DNA replication and episome tethering, but the extent of cell-type-specific regulation remains unclear. Here, we identify that KSHV hijacks the pioneering function of the endothelial-specific transcription factor SOX18 to facilitate persistence of viral episomes. Upon infection, LANA co-opts SOX18 to recruit the SWI/SNF chromatin-remodeling complex via its ATPase subunit BRG1, enhancing chromatin accessibility and enabling efficient viral genome persistence. Disruption of SOX18 or BRG1—genetically or pharmacologically—leads to reduced episome load and attenuated hallmarks of virus infection. This work highlights how viruses can harness lineage-specific transcriptional regulators to establish persistent nuclear retention of their episome into the host genome.

• Kauko, Otto; Turunen, Mikko; Pihlajamaa, Päivi; Häkkinen, Antti; Queiroz, Rayner M.L. & Pääkkönen, Mirva [Vis alle 19 forfattere av denne artikkelen] (2025). Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer. Science Advances. 11(34). doi: 10.1126/sciadv.adt1798. Fulltekst i vitenarkiv Vis sammendrag

  Mutations in numerous genes contribute to human cancer, with different oncogenic lesions prevalent in different cancer types. However, the malignant phenotype is simple, characterized by unrestricted cell growth, invasion, and often metastasis. One possible hypothesis explaining this dichotomy is that cancer genes regulate common targets, which then function as master regulators of essential cancer phenotypes. To identify mechanisms that drive the most fundamental feature shared by all tumors—unrestricted cell proliferation—we used a multiomic approach, which identified translation and ribosome biogenesis as common targets of major oncogenic pathways across cancer types. Proteomic analysis of tumors and functional studies of cell cultures established nucleolar and coiled-body phosphoprotein 1 as a key node, whose convergent regulation, both transcriptionally and posttranslationally, is critical for tumor cell proliferation. Our results indicate that lineage-specific oncogenic pathways regulate the same set of targets for growth control, revealing key downstream nodes that could be targeted for therapy or chemoprevention.

• Patel, Divyeshkumar Amrubthai; Tiusanen, Ville; Karttunen, Konsta; Pihlajamaa, Paivi & Sahu, Biswajyoti (2025). Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes. Communications Biology. 8. doi: 10.1038/s42003-025-08413-0. Fulltekst i vitenarkiv Vis sammendrag

  Derepression of transposable elements (TE) by epigenetic therapy leads to the activation of immune response in cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) in context of p53 is still elusive. Here, we used FDA-approved epigenetic drugs to systematically inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal, esophageal, and prostate cancer cells. We show that distinct TE subfamilies are derepressed by inhibition of different CMEs in cell type-specific manner. Co-inhibition of DNMT and HDAC (DNMTi-HDACi) had the most consistent effect across cancer types. Loss of p53 results in stronger TE activation and TE-chimeric transcript expression and this effect is largely mediated by the non-genomic actions of p53. Robust immune response elicited by DNMTi-HDACi is due to induced inverted repeat Alu expression concomitant with reduced ADAR1-mediated Alu RNA editing. Collectively, our systematic analyses provide insights for rational use of epigenetic therapies in distinct cancers.

• Karttunen, Konsta; Patel, Divyesh & Sahu, Biswajyoti (2024). Transposable elements as drivers of dedifferentiation: Connections between enhancers in embryonic stem cells, placenta, and cancer. Bioessays. ISSN 0265-9247. 46(10). doi: 10.1002/bies.202400059. Fulltekst i vitenarkiv Vis sammendrag

  Transposable elements (TEs) have emerged as important factors in establishing the cell type-specific gene regulatory networks and evolutionary novelty of embryonic and placental development. Recently, studies on the role of TEs and their dysregulation in cancers have shed light on the transcriptional, transpositional, and regulatory activity of TEs, revealing that the activation of developmental transcriptional programs by TEs may have a role in the dedifferentiation of cancer cells to the progenitor-like cell states. This essay reviews the recent evidence of the cis-regulatory TEs (henceforth crTE) in normal development and malignancy as well as the key transcription factors and regulatory pathways that are implicated in both cell states, and presents existing gaps remaining to be studied, limitations of current technologies, and therapeutic possibilities.

• Fei, Liangru; Zhang, Kaiyang; Hautaniemi, Sampsa & Sahu, Biswajyoti (2024). Protocol to identify defined reprogramming factor expression using a factor-indexing single-nuclei multiome sequencing approach. STAR Protocols. 5(3). doi: 10.1016/j.xpro.2024.103148. Fulltekst i vitenarkiv Vis sammendrag

  Ectopic expression of lineage-specific transcription factors (TFs) of another cell type can induce cell fate reprogramming. However, the heterogeneity of reprogramming cells has been a challenge for data interpretation and model evaluation. Here, we present a protocol to characterize cells expressing defined factors during direct cell reprogramming using a factor-indexing approach based on single-nuclei multiome sequencing (FI-snMultiome-seq). We describe the steps for barcoding TFs, converting human fibroblasts to pancreatic ductal-like cells using defined TFs, and preparing library for FI-snMultiome-seq analysis. For complete details on the use and execution of this protocol, please refer to Fei et al.1

• Karttunen, Konsta; Patel, Divyesh; Xia, Jihan; Fei, Liangru; Palin, Kimmo & Aaltonen, Lauri [Vis alle 7 forfattere av denne artikkelen] (2023). Transposable elements as tissue-specific enhancers in cancers of endodermal lineage. Nature Communications. 14. doi: 10.1038/s41467-023-41081-4. Fulltekst i vitenarkiv Vis sammendrag

  Transposable elements (TE) are repetitive genomic elements that harbor binding sites for human transcription factors (TF). A regulatory role for TEs has been suggested in embryonal development and diseases such as cancer but systematic investigation of their functions has been limited by their widespread silencing in the genome. Here, we utilize unbiased massively parallel reporter assay data using a whole human genome library to identify TEs with functional enhancer activity in two human cancer types of endodermal lineage, colorectal and liver cancers. We show that the identified TE enhancers are characterized by genomic features associated with active enhancers, such as epigenetic marks and TF binding. Importantly, we identify distinct TE subfamilies that function as tissue-specific enhancers, namely MER11- and LTR12-elements in colon and liver cancers, respectively. These elements are bound by distinct TFs in each cell type, and they have predicted associations to differentially expressed genes. In conclusion, these data demonstrate how different cancer types can utilize distinct TEs as tissue-specific enhancers, paving the way for comprehensive understanding of the role of TEs as bona fide enhancers in the cancer genomes.

• Fei, Liangru; Zhang, Kaiyang; Poddar, Nikita; Hautaniemi, Sampsa & Sahu, Biswajyoti (2023). Single-cell epigenome analysis identifies molecular events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells. Developmental Cell. ISSN 1534-5807. 58(18), s. 1701–1715. doi: 10.1016/j.devcel.2023.08.023. Fulltekst i vitenarkiv Vis sammendrag

  Cell fate can be reprogrammed by ectopic expression of lineage-specific transcription factors (TFs). However, the exact cell state transitions during transdifferentiation are still poorly understood. Here, we have generated pancreatic exocrine cells of ductal epithelial identity from human fibroblasts using a set of six TFs. We mapped the molecular determinants of lineage dynamics using a factor-indexing method based on single-nuclei multiome sequencing (FI-snMultiome-seq) that enables dissecting the role of each individual TF and pool of TFs in cell fate conversion. We show that transition from mesenchymal fibroblast identity to epithelial pancreatic exocrine fate involves two deterministic steps: an endodermal progenitor state defined by activation of HHEX with FOXA2 and SOX17 and a temporal GATA4 activation essential for the maintenance of pancreatic cell fate program. Collectively, our data suggest that transdifferentiation—although being considered a direct cell fate conversion method—occurs through transient progenitor states orchestrated by stepwise activation of distinct TFs.

• Gawriyski, Lisa; Jouhilahti, Eeva-Mari; Yoshihara, Masahito; Fei, Liangru; Weltner, Jere & Airenne, Tomi T. [Vis alle 20 forfattere av denne artikkelen] (2023). Comprehensive characterization of the embryonic factor LEUTX. iScience. 26(3). doi: 10.1016/j.isci.2023.106172. Fulltekst i vitenarkiv Vis sammendrag

  The paired-like homeobox transcription factor LEUTX is expressed in human preimplantation embryos between the 4- and 8-cell stages, and then silenced in somatic tissues. To characterize the function of LEUTX, we performed a multiomic characterization of LEUTX using two proteomics methods and three genome-wide sequencing approaches. Our results show that LEUTX stably interacts with the EP300 and CBP histone acetyltransferases through its 9 amino acid transactivation domain (9aaTAD), as mutation of this domain abolishes the interactions. LEUTX targets genomic cis-regulatory sequences that overlap with repetitive elements, and through these elements it is suggested to regulate the expression of its downstream genes. We find LEUTX to be a transcriptional activator, upregulating several genes linked to preimplantation development as well as 8-cell-like markers, such as DPPA3 and ZNF280A. Our results support a role for LEUTX in preimplantation development as an enhancer binding protein and as a potent transcriptional activator.

• Pihlajamaa, Päivi; Kauko, Otto; Sahu, Biswajyoti; Kivioja, Teemu & Taipale, Jussi (2022). A competitive precision CRISPR method to identify the fitness effects of transcription factor binding sites. Nature Biotechnology. ISSN 1087-0156. Fulltekst i vitenarkiv
• Sahu, Biswajyoti; Hartonen, Tuomo; Pihlajamaa, Päivi; Wei, Bei; Dave, Kashyap & Zhu, Fangjie [Vis alle 13 forfattere av denne artikkelen] (2022). Sequence determinants of human gene regulatory elements. Nature Genetics. ISSN 1061-4036. 54, s. 283–293. Fulltekst i vitenarkiv Vis sammendrag

  DNA can determine where and when genes are expressed, but the full set of sequence determinants that control gene expression is unknown. Here, we measured the transcriptional activity of DNA sequences that represent an ~100 times larger sequence space than the human genome using massively parallel reporter assays (MPRAs). Machine learning models revealed that transcription factors (TFs) generally act in an additive manner with weak grammar and that most enhancers increase expression from a promoter by a mechanism that does not appear to involve specific TF–TF interactions. The enhancers themselves can be classified into three types: classical, closed chromatin and chromatin dependent. We also show that few TFs are strongly active in a cell, with most activities being similar between cell types. Individual TFs can have multiple gene regulatory activities, including chromatin opening and enhancing, promoting and determining transcription start site (TSS) activity, consistent with the view that the TF binding motif is the key atomic unit of gene expression.

• Berta, Davide G.; Kuisma, Heli; Välimäki, Niko; Räisänen, Maritta; Jäntti, Maija & Pasanen, Annukka [Vis alle 27 forfattere av denne artikkelen] (2021). Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma. Nature. ISSN 0028-0836. Fulltekst i vitenarkiv
• Sahu, Biswajyoti; Pihlajamaa, Paivi; Zhang, Kaiyang; Palin, Kimmo; Ahonen, Saija & Cervera, Alejandra [Vis alle 10 forfattere av denne artikkelen] (2021). Human cell transformation by combined lineage conversion and oncogene expression. Oncogene. ISSN 0950-9232. Fulltekst i vitenarkiv
• Munne, Pauliina; Martikainen, Lahja; Räty, Iiris; Bertula, Kia; Nonappa & Ruuska, Janika [Vis alle 34 forfattere av denne artikkelen] (2021). Compressive stress-mediated p38 activation required for ERα+ phenotype in breast cancer. Nature Communications. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Sahu, Biswajyoti (2023). A molecular approach to genetic and epigenetic gene regulation, from basic research to the clinic. Fulltekst i vitenarkiv
• Sahu, Biswajyoti (2023). Single Cell Biology: From Development to Cancer. Fulltekst i vitenarkiv
• Sahu, Biswajyoti (2023). Multi-omic data analysis and integration for precision medicine. Fulltekst i vitenarkiv
• Sahu, Biswajyoti (2023). Molecular approach to study human cancers and the role of epigenome reprogramming. Fulltekst i vitenarkiv
• Sahu, Biswajyoti (2022). Sequence determinants of human gene regulatory elements and the role of transcription factors in cell fate control and cancer. Fulltekst i vitenarkiv
• Sahu, Biswajyoti (2022). A novel factor indexing multiome approach to dissect determinants of cell fate control. Fulltekst i vitenarkiv

Se alle arbeider i NVA