Biology subjects

Schwalbe, E. C.

Publications and source records attributed to Schwalbe, E. C..

3 recordsLinked to original sources

bioRxiv2024

Deconvolution of cancer methylation patterns determines that altered methylation in cancer is dominated by a non-disease associated proliferation signal

All cancers are associated with massive reorganisation of cellular epigenetic patterns, including extensive changes in the genomic patterns of DNA methylation. However, the huge scale of these changes has made it very challenging to identify key DNA methylation changes responsible for driving cancer development. Here, we present a novel approach to address this problem called methylation mapping. Through comparison of multiple types of B-lymphocyte derived malignancies and normal cell populations, this approach can define the origins of methylation changes as proliferation-driven, differentiation-driven and disease-driven (including both cancer-specific changes and cancer absent changes). Each of these categories of methylation change were found to occur at genomic regions that vary in sequence context, chromatin structure and associated transcription factors, implying underlying mechanistic differences behind the acquisition of methylation at each category. This analysis determined that only a very small fraction (about 3%) of DNA methylation changes in B-cell cancers are disease related, with the overwhelming majority (97%) being driven by normal biological processes, predominantly cell proliferation. Furthermore, the low level of true disease-specific changes can potentially simplify identification of functionally relevant DNA methylation changes, allowing identification of previously unappreciated candidate drivers of cancer development, as illustrated here by the identification and functional confirmation of SLC22A15 as a novel tumour suppressor candidate in acute lymphoblastic leukaemia. Overall, this approach should lead to a clearer understanding of the role of altered DNA methylation in cancer development, facilitate the identification of DNA methylation targeted genes with genuine functional roles in cancer development and thus identify novel therapeutic targets.

cancer biology↗

bioRxiv2022

Medulloblastoma Group 3 and 4 Tumors Comprise a Clinically and Biologically Significant Expression Continuum Reflecting Human Cerebellar Development

Medulloblastoma is currently sub-classified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA-seq in large well annotated cohorts of medulloblastoma we show that transcriptionally Group3 and Group4 medulloblastomas exist not as discrete types but as intermediates on a bipolar continuum between archetypal Group3 and Group4 entities. Continuum position is prognostic, reflects propensity for specific DNA copy-number changes, key switches in isoform/enhancer usage and RNA-editing. Examining scRNA-seq profiles we show intra-tumoral transcriptional heterogeneity along the continuum is limited in a subtype-dependent manner. By integrating with a human scRNA-seq reference atlas we show this continuum is mirrored by an equivalent continuum of transcriptional cell types in early fetal cerebellar development. We identify unique developmental niches for all four major subgroups and link each to a common developmental antecedent. Our findings show a transcriptional continuum arising from oncogenic disruption of highly specific fetal cerebellar cell types, linked to almost every aspect of Group3/Group4 molecular biology and clinico-pathology.

cancer biology↗

bioRxiv2022

The Idiopathic Pulmonary Fibrosis-associated single nucleotide polymorphism rs35705950 is transcribed in a MUC5B PromoterAssociated Long Non-Coding RNA(AC061979.1)

LncRNAs are involved in regulatory processes in the human genome, including gene expression. The rs35705950 SNP, previously associated with IPF, overlaps the recently annotated lncRNA AC061979.1, a 1,712 nucleotide transcript located within the MUC5B promoter at chromosome 11p15.5. To document the expression pattern of the transcript, we processed 3.9 TBases of publicly available RNA-SEQ data across 27 independent studies involving lung airway epithelial cells. Epithelial lung cells showed expression of this putative pancRNA. The findings were independently validated in cell lines and primary cells. The rs35705950 is found within a conserved region (from fish to primates) within the expressed sequence indicating functional importance. These results implicate the rs35705950-containing AC061979.1 pancRNA as a novel component of the MUC5B expression control minicircuitry.

cell biology↗