Biology subjects

Abraham, K. J.

Publications and source records attributed to Abraham, K. J..

3 recordsLinked to original sources

bioRxiv2021

Locus-associated R-loop repression in cis

R-loops exert varied beneficial or detrimental effects. To assess the function of an R-loop at a specific genetic locus, we had developed an inducible RNaseH1-EGFP-dCas9 (RED) protein chimaera as part of a locus-associated R-loop-modulating system (LasR). LasR is compatible with R-loop modulation in trans, which targets RED to one locus to repress R-loops at another spatially proximal site. Here we use the LasR system for R-loop modulation in cis, which consists of targeting RED directly to an R-loop. The combination of LasR in cis and trans will be essential to ascribe functions to specific R-loops within varied molecular contexts and study designs.

molecular biology↗

bioRxiv2020

Optimizing Sequencing Resources in Genotyped Livestock Populations Using Linear Programming

BackgroundLow-cost genome-wide single-nucleotide polymorphisms (SNPs) are routinely used in animal breeding programs. Compared to SNP arrays, the use of whole-genome sequence data generated by the next-generation sequencing technologies (NGS) has great potential in livestock populations. However, a large number of animals are required to be sequenced to exploit the full potential of whole-genome sequence data. Thus, novel strategies are desired to allocate sequencing resources in genotyped livestock populations such that the entire population can be sequenced or imputed efficiently. MethodsWe present two applications of linear programming models called LPChoose for sequencing resources allocation. The first application is to identify the minimum number of animals for sequencing while meeting the criteria that each haplotype in the population is contained in at least one of the animals selected for sequencing. The second is to sequence a fixed number of animals whose haplotypes include as large a proportion as possible of the haplotypes present in the population given a limited sequencing budget. ResultsIn both applications LPChoose has similar or better performance than some other methods. The linear programming models we proposed are based on rigorous and well defined optimization techniques and easy and straightforward to implement. LPChoose is available as an open-source package.

genomics↗

bioRxiv2019

Identification of a small molecule antagonist for the Tudor domain of SMN

Survival of motor neuron (SMN), a Tudor-domain-containing protein, plays an important role in diverse biological pathways via recognition of symmetrically dimethylated arginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to the motor neuron degenerative disease spinal muscular atrophy (SMA). Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that the sandwich stacking interactions of SMN and compound 1 play a critical role in selective binding to SMN. Various on-target engagement assays support that compound 1 recognizes SMN specifically in a cellular context. In cell studies display that the SMN antagonist prevent the interaction of SMN with R1810me2s of DNA-directed RNA polymerase II subunit POLR2A and results in transcription termination and R-loop accumulation, mimicking depletion of SMN. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, the potent SMN antagonist could be used as an efficient tool in understanding the biological functions of SMN and molecular etiology in SMA.

biochemistry↗