ABI1 regulates transcriptional activity of Androgen Receptor by novel DNA and AR binding mechanism [RNA-seq]
Transcription regulates key functions of living organisms in normal and disease states, including cell growth and development, embryonic and adult tissue organization, and tumor progression. Here we identify a novel mechanism of transcriptional regulation by an actin regulatory and signaling protein, Abelson Interactor 1(ABI1). Using prostate cancer models, we uncover a reciprocal regulation between ABI1 and the Androgen Receptor (AR). ABI1 is a direct, androgen-regulated target; in turn, ABI1 interacts with AR and its splice variant ARv7, and co-regulates a subset of specific transcriptional targets. ABI1 directs transcription through transient yet well-defined interaction of its intrinsically disordered region with DNA. Clinical evaluation shows that both the ABI1-DNA binding (through Exon 4 splicing) and ABI1-AR interaction are regulated during androgen deprivation therapy and prostate cancer progression, thus controlling tumor plasticity through connecting actin cytoskeleton and cellular signaling to transcriptional regulation. We propose that ABI1 is an epigenetic regulator of transcriptional homeostasis in AR-driven cancers. Overall design: Total RNA was extracted from LNCaP cell lines following treatmenet with DMSO or 1 nM synthetic androgen R1881 using the Qiagen Qiashredder and RNAeasy Extraction Kit (Qiagen). Statistical and quality control analysis was performed using Partek bioinformatics software. Unaligned reads were trimmed based on quality score(min quality phred score=20); STAR alignment was performed with quantification to annotation model using refseq annotation (Partek E/M); features were filtered to remove if maximum <=10 and normalized using CPM + 0.0001; differential expression analysis was performed using treatment and cell type as attributes using DESeq2