TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41.
TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41.
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DOI：
10.1016/j.celrep.2020.108371
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发表时间：
2020-11-10
期刊：
影响因子：
8.8
通讯作者：
Xavier RJ
中科院分区：
文献类型：
--
作者：
Carey KL;Paulus GLC;Wang L;Balce DR;Luo JW;Bergman P;Ferder IC;Kong L;Renaud N;Singh S;Kost-Alimova M;Nyfeler B;Lassen KG;Virgin HW;Xavier RJ
转录因子EB（TFEB）激活溶酶体生物发生基因响应环境线索。考虑到TFEB信号传导受损和溶酶体功能障碍在代谢、神经和感染性疾病中的影响，我们的目标是通过检查对TFEB亚细胞定位和刺激的转录反应来系统地识别TFEB指导的电路。我们发现，稳态核TFEB足以激活溶酶体，自噬和先天免疫基因的转录，而其他目标需要更高的刺激阈值。此外，我们确定了mTOR抑制和细菌自噬之间共享和不同的转录特征。使用全基因组CRISPR文库，我们发现TFEB靶点可以保护细胞免受溶酶体细胞死亡或使细胞对溶酶体细胞死亡敏感。BHLHE 40和BHLHE 41是对高、持续水平的核TFEB有反应的基因，在溶酶体细胞死亡诱导后与TFEB相反。进一步的研究鉴定了TFEB和BHLHE 40/41反调节的基因，将这种负反馈添加到目前对TFEB调节机制的理解中。采用RNA测序，全基因组CRISPR筛选和高含量亚细胞成像，Carey等人系统地揭示了对TFEB的定位和刺激特异性转录反应，包括稳态下的靶基因激活。作者进一步揭示了BHLHE 40和BHLHE 41的负反馈环，其抵消了溶酶体应激诱导的TFEB转录特征。
Transcription factor EB (TFEB) activates lysosomal biogenesis genes in response to environmental cues. Given implications of impaired TFEB signaling and lysosomal dysfunction in metabolic, neurological, and infectious diseases, we aim to systematically identify TFEB-directed circuits by examining transcriptional responses to TFEB subcellular localization and stimulation. We reveal that steady-state nuclear TFEB is sufficient to activate transcription of lysosomal, autophagy, and innate immunity genes, whereas other targets require higher thresholds of stimulation. Furthermore, we identify shared and distinct transcriptional signatures between mTOR inhibition and bacterial autophagy. Using a genome-wide CRISPR library, we find TFEB targets that protect cells from or sensitize cells to lysosomal cell death. BHLHE40 and BHLHE41, genes responsive to high, sustained levels of nuclear TFEB, act in opposition to TFEB upon lysosomal cell death induction. Further investigation identifies genes counter-regulated by TFEB and BHLHE40/41, adding this negative feedback to the current understanding of TFEB regulatory mechanisms. Employing RNA sequencing, genome-wide CRISPR screening, and high-content subcellular imaging, Carey et al. systematically unravel localization- and stimulation-specific transcriptional responses to TFEB, including target gene activation at steady state. The authors further uncover a negative feedback loop by BHLHE40 and BHLHE41 that counteracts a TFEB transcriptional signature induced by lysosomal stress.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
4.6
作者：
Fernández-Mosquera L;Diogo CV;Yambire KF;Santos GL;Luna Sánchez M;Bénit P;Rustin P;Lopez LC;Milosevic I;Raimundo N
通讯作者：
Raimundo N