Enhancing Sox/Oct cooperativity induces higher-grade developmental reset

SOX2 重编程 诱导多能干细胞 KLF4公司 转录因子 生物 细胞生物学 突变体 胚胎干细胞 细胞 遗传学 基因
作者
Caitlin M. MacCarthy,Vikas Malik,Guangming Wu,Taras Velychko,Gal Keshet,Ralf Jauch,Vlad Cojocaru,Hans R. Schöler,Sergiy Velychko
标识
DOI:10.1101/2022.09.23.509242
摘要

ABSTRACT The discovery of induced pluripotent stem cell (iPSC) technology by Shinya Yamanaka has truly enabled the stem cell field. After 16 years of intense research, the delivery methods and culture media have improved but the original factors—Oct4, Sox2, Klf4, and Myc (OSKM)—remain central for driving reprogramming. Here we define structural elements in chimeric Sox2/Sox17 transcription factors that rescued the ability of nonfunctional Oct factors to induce pluripotency. Most importantly, we discovered a single amino acid swap in the DNA-binding domain of Sox2, A61V, that stabilizes the Sox/Oct heterodimer on DNA through hydrophobic interaction with Oct. The highly cooperative Sox2 AV mutant enables iPSC generation with Oct4 orthologs, such as Oct2 and Oct6, as well as rescues otherwise detrimental Oct4 mutants and domain deletions. Sox2 AV has a dramatic effect on the cell fate reset, significantly improving the developmental potential of OSKM iPSCs. Moreover, by swapping multiple beneficial elements of Sox17 into Sox2 we have built a chimeric super-SOX factor—Sox2-17—that delivers unprecedented reprogramming efficiency and kinetics in five tested species. Sox2-17 enhances five-, four-, and three-factor reprogramming up to hundreds of times, enables two-factor generation of human iPSCs, and allows integration-free reprogramming of otherwise non-permissive aged human, non-human primate, and cattle fibroblasts. Our study demonstrates that a complete developmental reset requires both robust activation of regulatory elements controlled by the canonical SoxOct motif and limiting cellular proliferation driven by Oct4 and Myc. A high level of Sox2 expression and Sox2/Oct4 heterodimerization emerge as the key determinants of high-grade pluripotency that fades along the naïve-to-primed continuum. Transient expression of SK cocktail can restore the naivety, providing a powerful technology to induce more complete developmental reset in pluripotent cells across species.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
Lily发布了新的文献求助10
1秒前
1秒前
kkkkk发布了新的文献求助500
2秒前
lovelife完成签到,获得积分10
2秒前
Summer_Xia完成签到,获得积分10
3秒前
时光完成签到,获得积分10
6秒前
like发布了新的文献求助10
7秒前
zj给Agee_Feng的求助进行了留言
7秒前
8秒前
9秒前
luopengdong完成签到,获得积分20
9秒前
cctv18应助苏素采纳,获得10
9秒前
11秒前
隐形曼青应助huco采纳,获得10
12秒前
kingripple发布了新的文献求助10
13秒前
xiaolaoshuboshi完成签到,获得积分10
13秒前
14秒前
愤怒的稀完成签到,获得积分10
17秒前
小奕完成签到,获得积分10
18秒前
海与星发布了新的文献求助10
19秒前
末岛发布了新的文献求助30
20秒前
海鲜完成签到,获得积分10
22秒前
小马甲应助Bellala采纳,获得10
23秒前
23秒前
24秒前
26秒前
Costing发布了新的文献求助10
27秒前
28秒前
今天没烦恼完成签到,获得积分10
28秒前
研友_X89o6n发布了新的文献求助10
30秒前
30秒前
like完成签到,获得积分10
32秒前
32秒前
LIU完成签到,获得积分10
33秒前
34秒前
34秒前
个性的紫菜应助左左先生采纳,获得10
34秒前
烟花应助坦率斑马采纳,获得10
37秒前
852应助奎尼丁采纳,获得10
37秒前
C120发布了新的文献求助10
37秒前
高分求助中
The three stars each : the Astrolabes and related texts 1070
Hieronymi Mercurialis de Arte Gymnastica Libri Sex: In Quibus Exercitationum Omnium Vetustarum Genera, Loca, Modi, Facultates, Et Quidquid Deniq. Ad ... Diligenter Explicatur (Classic Reprint) Paperback – 23 April 2018 1000
Manual of Clinical Microbiology, 4 Volume Set (ASM Books) 13th Edition 1000
Hieronymi Mercurialis Foroliviensis De arte gymnastica libri sex: In quibus exercitationum omnium vetustarum genera, loca, modi, facultates, & ... exercitationes pertinet diligenter explicatur Hardcover – 26 August 2016 900
De arte gymnastica. The art of gymnastics 600
Boris Pesce - Gli impiegati della Fiat dal 1955 al 1999 un percorso nella memoria 500
[Lambert-Eaton syndrome without calcium channel autoantibodies] 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 有机化学 工程类 生物化学 纳米技术 物理 内科学 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 电极 光电子学 量子力学
热门帖子
关注 科研通微信公众号,转发送积分 2403030
求助须知:如何正确求助?哪些是违规求助? 2102077
关于积分的说明 5302870
捐赠科研通 1829628
什么是DOI,文献DOI怎么找? 911818
版权声明 560421
科研通“疑难数据库(出版商)”最低求助积分说明 487448