Biology subjects

Forcier, T.

Publications and source records attributed to Forcier, T..

4 recordsLinked to original sources

bioRxiv2026

TEsingle enables locus-specific transposable element expression analysis at single-cell resolution

Transposable elements (TEs) are mobile genetic sequences that can generate new copies of themselves via insertional mutations. These viral-like sequences comprise nearly half the human genome and are present in most genome wide sequencing assays. While only a small fraction of genomic TEs have retained their ability to transpose, TE sequences are often transcribed from their own promoters or as part of larger gene transcripts. Accurately assessing TE expression from each individual genomic TE locus remains an open problem in the field, due to the highly repetitive nature of these multi-copy sequences. These issues are compounded in single-cell and single-nucleus transcriptome experiments, where additional complications arise due to sparse read coverage and unprocessed mRNA introns. Here we present our tool for single-cell TE and gene expression analysis, TEsingle. Using synthetic datasets, we show the problems that arise when not properly accounting for intron retention events, failing to address uncertainty in alignment scoring, and failing to make use of unique molecular identifiers for transcript resolution. Addressing these challenges has enabled an accurate TE analysis suite that simultaneously tracks gene expression as well as locus-specific resolution of expressed TEs. We showcase the performance of TEsingle using single-nucleus profiles from substantia nigra (SN) tissues of Parkinsons Disease (PD) patients. We find examples of young and intact TEs that mark dopaminergic neurons (DA) as well as many young TEs from the LINE and ERV families that are elevated in PD neurons and glia. These results demonstrate that TE expression is highly cell-type and cellular-state specific and elevated in particular subsets of neurons, astrocytes, and microglia from PD patients.

genomics↗

bioRxiv2025

Activation of transposable elements is linked to a region- and cell-type-specific interferon response in Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TE) have been linked to inflammation, but their potential role in PD remains unexplored. Using bulk- and single-nuclei RNAseq of postmortem brain tissue from four brain regions, we studied TE transcription and its correlation with PD neuroinflammation. Over a thousand TEs, including LINE-1s and ERVs, were expressed in a cell-type and region-specific manner in the human brain. Increased TE expression was found in microglia and neurons in the substantia nigra and putamen of PD brains, but not amygdala or prefrontal cortex, compared to controls. This TE activation correlated with an innate immune response in the same brain regions. The link between an interferon response and TE activation was mechanistically confirmed using human pluripotent stem cell-derived microglia and neurons. Our findings provide insights into TE transcription in the PD brain and suggest TEs may contribute to neuroinflammation and pathological progression in PD. Teaser: Transposable elements are linked to a cell type specific inflammatory state in Parkinsons Disease.

neuroscience↗

bioRxiv2018

Precision measurement of cis-regulatory energetics in living cells

Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of \"allelic manifolds\", a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP and {sigma}70 RNA polymerase. Doing so, we consistently obtained energetic measurements precise to ~ 0.1 kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.

biophysics↗

bioRxiv2017

Mutational sequencing for accurate count and long-range assembly

We introduce a new protocol, mutational sequencing or muSeq, which randomly deaminates unmethylated cytosines at a fixed and tunable rate. The muSeq protocol marks each initial template molecule with a unique mutation signature that is present in every copy of the template, and in every fragmented copy of a copy. In the sequenced read data, this signature is observed as a unique pattern of C-to-T or G-to-A nucleotide conversions. Clustering reads with the same conversion pattern enables accurate count and long-range assembly of initial template molecules from short-read sequence data. We explore count and low-error sequencing by profiling a 135,000 fragment PstI representation, demonstrating that muSeq improves copy number inference and significantly reduces sporadic sequencer error. We explore long-range assembly in the context of cDNA, generating contiguous transcript clusters greater than 3,000 bp in length. The muSeq assemblies reveal transcriptional diversity not observable from short-read data alone.

genomics↗