Jacob Loupe

Excited to share our work @hudsonalpha profiling >100 #TranscriptionFactors in the human brain using #ChIPseq! Cell type-specific binding profiles link TFs to neuropsychiatric diseases. @RickMyers_PhD @Ashlyn_Anderso @LindsayRizzardi biorxiv.org/content/10.110…

Excited to share our latest work is published @GenomeResearch! We explored allele-specific transcription factor binding across nine brain regions, offering new insights into gene regulation and the role of genetic variation in the brain genome.cshlp.org/content/34/8/1… 1/

Inarguably the most important human genetics paper of the year, and a landmark moment in the history of neurodevelopmental disorder (NDD) genetics. Mutations in RNU4-2, encoding a small nuclear RNA (snRNA) are among the most frequent genetic causes of NDD, explaining up to 0.4% of all cases. Yet, these variants have not been found all these years, despite the big advancements in genome sequencing in the past years. The mind-blowing part: just a region of 18 base pairs that encode a critical part of the snRNA holds all the NDD mutations, a majority of them are insertion mutations. A 18bp noncoding region explaining 0.4% of all NDDs is really huge. This knowledge will solve (already solving) genetic diagnoses of thousands of NDD patients around the world. The 18-bp region is highly constrained. Natural selection is actively removing the mutations from the population, yet the region keeps mutating again and again and again. The next important follow up will be to find what drives such a high mutation rate in this region, particularly insertion mutations. The authors add a new twist to the story: the majority of the maternally inherited. This is surprising, as the origins of NDDs are typically paternally biased. The mechanism is going to be absolutely mind-blowing. Congrats Nicky and team on this remarkable work. This is one of the biggest success stories of 100k genomes project by Genomics England. Whole genome sequencing is already making a big impact in the rare disease space!

I'm excited to share our new publication in @CellGenomics! We examine the structure-function relationship between chromatin looping and RNA polymerase II-mediated gene expression during neural lineage commitment. Check it out! doi.org/10.1016/j.xgen…

Single-cell profiling of H3K27ac, H3K27me3 and H3K4me3 histone modifications from progenitor to differentiated neural fates in human brain and retina #organoid models @TreutleinLab @GrayCampLab @joschf @EpiGN_lab @ETHZ nature.com/articles/s4159…

Very excited to share this new preprint led by the super talented @klbrida. We started by asking what marks drug-activated ensembles and stumbled onto a surprising answer that identified a key regulator of neuronal excitability and reward. A brief 🧵... biorxiv.org/content/10.110…

Explore BrainTF, a valuable resource for understanding gene regulation in the human brain. doi.org/10.7303/syn519… @Ashlyn_Anderso @LindsayRizzardi @RickMyers_PhD @hudsonalpha 5/5

We discovered that TFs such as TBR1 and PKNOX1 are enriched at risk variants linked to psychiatric disorders, suggesting their potential role in disease mechanisms and highlighting the importance of these TFs in understanding neurological disease. 4/

Key findings include unique binding patterns of neuronal TFs SATB2 and TBR1 in regions depleted of HOT sites. These regions are essential for promoting neuronal gene expression and highlight the importance of studying TF behavior in relevant cell types. 3/

Excited to share our paper #BrainTF is published in @NatureNeuro. We profiled #TF binding using ChIP-seq for over 100 TFs across 9 brain regions, along with ATAC-seq, RNA-seq, and DNA methylation on postmortem human brain tissue. nature.com/articles/s4159… 1/

We include binding maps from bulk tissues and sorted #neurons (NeuN+), oligo (Olig2+), and #microglia/#astrocytes (NeuN-/Olig2-). We identified high occupancy target (HOT) sites, which are crucial for understanding TF selectivity and prioritizing targets for future research. 2/

A multiomic resource (ChIP–seq, ATAC-seq, RNA-seq, DNA methylation) on bulk tissues and sorted nuclei from several human postmortem brain regions, including binding maps for more than 100 transcription factors @JLoupe2 @hudsonalpha #BrainTF nature.com/articles/s4159…

Excited to share our preprint proposing pgBoost, an eQTL-informed gradient boosting model that integrates scores from single-cell enhancer-gene linking methods and genomic distance to predict regulatory SNP-gene links (a key step in interpreting GWAS discoveries)!🧬 1/4

Excited to share our #SingleCell dissection of #Schizophrenia, out in @ScienceMagazine today, reporting 470k cells in 27 cell types across 140 individuals from 2 cohorts, revealing key insights on #ExcitatoryNeurons, #NeuroDevelopment, #Synapses, #1Cmetabolism, #Genetics, #Subtyping, #NetworkConvergence, #TFs, #DEGs, #GWAS, #RareVariants, and #DiseaseMechanism, with @Brad_Ruzicka @LabRoussos @ShahinMohammadi @_josedavila #PsychENCODE2 Paper: science.org/doi/10.1126/sc… Collection: science.org/collections/ps… Science tweet: x.com/sciencemagazin… Big thanks to @NIH, @NIMHgov, #PsychENCODE

Finally out in @naturemethods from the brilliant @jb_lalanne & @SRegalad0, our highly quantitive single cell MPRA (scQer), applied to mammalian embryoids to find autonomous enhancers. Bonus = Tornado circular barcodes that are all kinds of useful. OA link: rdcu.be/dHqo1

Could not be more delighted to present our work investigating how over 220,000 complex and molecular trait-associated genetic variants affect transcriptional regulation using massively parallel reporter assays! biorxiv.org/content/10.110… See below for a 🧵. 1/n

Our #BICCN paper is out at @NatureNeuro Led by @noush_joglekar+@rainryuhei_wen. Single-cell isoforms across brain regions,development&species. nature.com/articles/s4159… #LongRead #RNA @iRnaCosi #nanopore #pacbio #genomics #Transcripomics #RNAseq #Splicing Thank you @ElisaFlo04 !

"caQTLs and haQTLs capture regulatory variations not associated with eQTLs and explain ∼49% of the functionally annotated GWAS loci" Been clear for a while that accessibility & histone marks provide more info for explaining & fine mapping GWAS loci than expression. 1/

Excited and proud to share our #SingleCell dissection of #ALS and #FTLD out in #Cell this week, across 620,000 cells, 44 cell types, 73 donors, and two brain regions. Although ALS affects #movement vs. FTLD #cognition, the two are nearly identical in the cell types, genes, and pathways they affect, both in #familial (monogenic) and in #sporadic (polygenic) cases, providing hope and candidate targets for common #therapeutic programs, implicating #LongRange-projecting neurons, and #cilia genes and pathways, necessary for their growth, but also #vascular changes and blood-brain-barrier function and integrity. News: news.mit.edu/2024/als-ftld-… Paper: cell.com/cell/abstract/… Preprint: doi.org/10.1101/2021.0… Data: synapse.org/#!Synapse:syn5… #NeuroDegeneration #ADRD #Alzheimers #FTD #FrontoTemporalDementia #LouGehrigsDisease #MyriamHeiman #SebastianPineda #VeroniqueBelzil #LiveLikeLou @iamalsorg @bsw5020 @alsadvocacy @ProjectALSorg #MotorCortex #BetzCells #VENs #C9orf72 #TDP43 #NeuroDegen #MCx @MTPA_US @NIH @NIHAging @GerstnerFdn @PackardFdn

Recent changes to #scRNAseq quantification tools can leave one dizzy. In biorxiv.org/content/10.110… w/ @DelaneyKSull, @kreldjarn, @NikhilaSwarna, @GuillaumOleSan & @pmelsted we clarify what kallisto, Cell Ranger, salmon/alevin and STARsolo are doing and how they're performing. 1/🧵