MADS-box transcriptional regulation of dimorphic transition in Penicillium marneffei

马尔尼菲青霉二态性转变的 MADS-box 转录调控

• 批准号: 9303893
• 负责人: James Jing Cai
• 金额: $ 16.71万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-27 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303893
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Anemia; Area; Body Temperature; Cellular Morphology; ChIP-seq; Clinical; DNA; Data; Development; Diagnostic; Evolution; Family; Fever; Foundations; Future; Gene Deletion; General Population; Genes; Genetic; Genomic Segment; Genomics; Goals; Growth; HIV Infections; Hospital Mortality; Immune; Immunocompromised Host; Immunosuppression; Individual; Infection; Investigation; Knowledge; Link; Liver; Maps; Methods; Molecular; Morphogenesis; Morphology; Mutation; Mycoses; Pathogenicity; Patients; Penicillium; Phase; Phase Transition; Phylogenetic Analysis; Play; Process; Public Health; Reporting; Research; Role; Southeastern Asia; Swelling; System; Techniques; Temperature; Testing; Therapeutic; Transcriptional Regulation; Virulence; Yeasts; base; dimorphism; effective intervention; expectation; fungus; gain of function; genome sequencing; innovation; latent infection; loss of function; loss of function mutation; lymph nodes; mortality; mouse model; mutant; novel; overexpression; pathogen; prevent; skin lesion; transcription factor; transcriptome sequencing; transmission process; whole genome

Systemic dimorphic fungi collectively cause over one million new infections every year. Latent infections worldwide grow to the tens of millions, making them a priority for today's research. Penicillium marneffei (Pm) is of particular concern due to a marked increase in the number of cases of penicilliosis in the last 20 years, which has been concurrent with the rise in immunosuppression due to the global spread of HIV infections. Pm grows as hypha in its environmental reservoir and as yeast in mammalian hosts. The phase transition between the two growth forms is considered to be essential for its pathogenicity and the transmission of penicilliosis. The transition between hypha and yeast is reversible and can be triggered at a sharp threshold temperature of 37°C. The precise mechanisms underlying the thermosensing and the phase transition in Pm remain unknown. Therefore, there is a critical need to identify key genes and regulatory processes involved in the morphogenetic control in Pm. The applicants' recent findings provide a promising, new opportunity for target identification. Using an innovative, serial culture-based experimental evolution (EE) technique, the applicants derived mutant Pm strains that undergo the hypha-to-yeast phase transition at 30°C rather than 37°C. DNA- and RNA- sequencing of the mutant and wild-type strains revealed important roles of a family of MADS-box transcription factor (TF) genes, especially madsB and madsA, in regulating thermal dimorphism in Pm. The expression of madsB in wild type is up-regulated 1,500-fold during the hypha-to-yeast transition. The madsB loss-of-function mutation caused by genomic deletion in mutant strains seems to be responsible for the lower threshold temperature of phase transition. Significantly, EE-derived mutants are found to be completely avirulent in the mouse model, suggesting that the precise threshold temperature at 37°C for the phase transition is essential for Pm to infect and/or adapt to the host condition. Furthermore, the overexpression of madsA causes Pm to grow as hypha instead of yeast at 37°C. These preliminary data led to the central hypothesis that the Pm thermosensing systems act through temperature-responsive activities of the MADS-box TFs. Based on these preliminary results, the applicants propose the following two Specific Aims: (1) determine the roles of madsB and madsA in regulating thermal dimorphism in Pm, and (2) identify the downstream targets of MadsB and MadsA. Upon completion of the proposed research, the applicants expect to critically test the functions of the two MADS-box TFs in regulating dimorphic development in Pm (Aim 1). The applicants will identify the downstream targets of MadsB and/or MadsA, and examine the functions of selected targets in Pm (Aim 2). Together, these results will provide much-needed entry points to further investigate the otherwise mysterious mechanisms underlying thermal dimorphism in this important but understudied fungal pathogen.

系统性二态性真菌每年总共引起超过一百万个新感染。潜伏感染 全球范围内的人数已增至数千万，这使他们成为当今研究的重点。马尔尼菲青霉 (Pm) 由于过去 20 年来青霉病病例数量显着增加，因此特别令人关注， 与此同时，由于艾滋病毒感染的全球蔓延，免疫抑制现象也随之增加。下午 在其环境储存库中作为菌丝生长，在哺乳动物宿主中作为酵母生长。之间的相变 这两种生长形式被认为对其致病性和青霉病的传播至关重要。 菌丝和酵母之间的转变是可逆的，并且可以在急剧的阈值温度下触发 37°C。 Pm 热传感和相变的精确机制仍然未知。 因此，迫切需要识别形态发生中涉及的关键基因和调控过程。 控制在下午。申请人最近的发现为目标识别提供了一个有希望的新机会。 使用创新的、基于连续培养的实验进化（EE）技术，申请人衍生出突变体 Pm 菌株在 30°C（而不是 37°C）下经历菌丝到酵母的相变。 DNA-和RNA- 突变株和野生型菌株的测序揭示了 MADS-box 转录家族的重要作用 因子（TF）基因，特别是 madsB 和 madsA，在调节 Pm 的热二态性中。的表达式为 野生型的 madsB 在菌丝到酵母的转变过程中上调 1,500 倍。 madsB 功能丧失 突变株基因组缺失引起的突变似乎是导致阈值较低的原因 相变温度。值得注意的是，EE 衍生的突变体被发现在 小鼠模型，表明 37°C 的精确相变阈值温度至关重要 Pm 感染和/或适应宿主条件。此外，madsA 的过度表达会导致 Pm 在 37°C 下以菌丝而非酵母形式生长。这些初步数据得出了一个中心假设：总理 热传感系统通过 MADS-box TF 的温度响应活动发挥作用。基于这些 根据初步结果，申请人提出以下两个具体目标：（1）确定madsB的角色 和 madsA 调节 Pm 热二态性的作用，以及 (2) 确定 MadsB 和 MadsB 的下游靶标 麦德斯A.完成拟议的研究后，申请人希望严格测试该功能 两个 MADS-box TF 调节 Pm 的二态性发育（目标 1）。申请人将确定 MadsB 和/或 MadsA 的下游靶标，并检查 Pm 中选定靶标的功能（目标 2）。 总之，这些结果将为进一步调查原本神秘的现象提供急需的切入点。 这种重要但尚未得到充分研究的真菌病原体热二态性的机制。

项目成果

Novel Partitivirus Enhances Virulence of and Causes Aberrant Gene Expression in Talaromyces marneffei.

• DOI: 10.1128/mbio.00947-18
• 发表时间: 2018-06-12
• 期刊: mBio
• 影响因子: 6.4
• 作者: Lau SKP;Lo GCS;Chow FWN;Fan RYY;Cai JJ;Yuen KY;Woo PCY
• 通讯作者: Woo PCY

Simulating variance heterogeneity in quantitative genome wide association studies.

• DOI: 10.1186/s12859-018-2061-1
• 发表时间: 2018-03-21
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Al Kawam A;Alshawaqfeh M;Cai JJ;Serpedin E;Datta A
• 通讯作者: Datta A

Expression profiling of disease progression in canine model of Duchenne muscular dystrophy.

• DOI: 10.1371/journal.pone.0194485
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Brinkmeyer-Langford C;Chu C;Balog-Alvarez C;Yu X;Cai JJ;Nabity M;Kornegay JN
• 通讯作者: Kornegay JN

AEGS: identifying aberrantly expressed gene sets for differential variability analysis.

AEGS：识别异常表达的基因集以进行差异变异性分析

• DOI: 10.1093/bioinformatics/btx646
• 发表时间: 2018-03-01
• 期刊: Bioinformatics (Oxford, England)
• 作者: Guan J;Chen M;Ye C;Cai JJ;Ji G
• 通讯作者: Ji G