Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
BMC Genomics. 2012 Aug 16;13:396. doi: 10.1186/1471-2164-13-396.
Drug susceptible clinical isolates of Candida albicans frequently become highly tolerant to drugs during chemotherapy, with dreadful consequences to patient health. We used RNA sequencing (RNA-seq) to analyze the transcriptomes of a CDR (Candida Drug Resistance) strain and its isogenic drug sensitive counterpart.
RNA-seq unveiled differential expression of 228 genes including a) genes previously identified as involved in CDR, b) genes not previously associated to the CDR phenotype, and c) novel transcripts whose function as a gene is uncharacterized. In particular, we show for the first time that CDR acquisition is correlated with an overexpression of the transcription factor encoding gene CZF1. CZF1 null mutants were susceptible to many drugs, independently of known multidrug resistance mechanisms. We show that CZF1 acts as a repressor of β-glucan synthesis, thus negatively regulating cell wall integrity. Finally, our RNA-seq data allowed us to identify a new transcribed region, upstream of the TAC1 gene, which encodes the major CDR transcriptional regulator.
Our results open new perspectives of the role of Czf1 and of our understanding of the transcriptional and post-transcriptional mechanisms that lead to the acquisition of drug resistance in C. albicans, with potential for future improvements of therapeutic strategies.
白色念珠菌对药物敏感的临床分离株在化疗过程中经常对药物产生高度耐受性，这对患者的健康造成了可怕的后果。我们使用 RNA 测序 (RNA-seq) 分析了 CDR（念珠菌耐药性）菌株及其同基因药物敏感对照物的转录组。
RNA-seq 揭示了 228 个基因的差异表达，包括 a) 先前鉴定为参与 CDR 的基因，b) 先前与 CDR 表型无关的基因，和 c) 功能尚未确定的新转录本。特别是，我们首次表明，CDR 的获得与转录因子编码基因 CZF1 的过度表达相关。CZF1 缺失突变体对许多药物敏感，与已知的多药耐药机制无关。我们表明 CZF1 作为 β-葡聚糖合成的抑制剂起作用，从而负调控细胞壁完整性。最后，我们的 RNA-seq 数据使我们能够鉴定 TAC1 基因上游的一个新转录区域，该区域编码主要的 CDR 转录调节剂。
我们的结果为 Czf1 的作用以及我们对导致白色念珠菌获得药物耐药性的转录和转录后机制的理解开辟了新的视角，为未来改善治疗策略提供了潜力。
