A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)

Ming Ru Wu; Lior Nissim; Doron Stupp; Erez Pery; Adina Binder-Nissim; Karen Weisinger; Casper Enghuus; Sebastian R. Palacios; Melissa Humphrey; Zhizhuo Zhang; Eva Maria Novoa; Manolis Kellis; Ron Weiss; Samuel D. Rabkin; Yuval Tabach; Timothy K. Lu

doi:10.1038/s41467-019-10912-8

A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)

Ming Ru Wu, Lior Nissim, Doron Stupp, Erez Pery, Adina Binder-Nissim, Karen Weisinger, Casper Enghuus, Sebastian R. Palacios, Melissa Humphrey, Zhizhuo Zhang, Eva Maria Novoa, Manolis Kellis, Ron Weiss, Samuel D. Rabkin, Yuval Tabach, Timothy K. Lu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Cell state-specific promoters constitute essential tools for basic research and biotechnology because they activate gene expression only under certain biological conditions. Synthetic Promoters with Enhanced Cell-State Specificity (SPECS) can be superior to native ones, but the design of such promoters is challenging and frequently requires gene regulation or transcriptome knowledge that is not readily available. Here, to overcome this challenge, we use a next-generation sequencing approach combined with machine learning to screen a synthetic promoter library with 6107 designs for high-performance SPECS for potentially any cell state. We demonstrate the identification of multiple SPECS that exhibit distinct spatiotemporal activity during the programmed differentiation of induced pluripotent stem cells (iPSCs), as well as SPECS for breast cancer and glioblastoma stem-like cells. We anticipate that this approach could be used to create SPECS for gene therapies that are activated in specific cell states, as well as to study natural transcriptional regulatory networks.

Original language	English
Article number	2880
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10912-8
State	Published - 1 Dec 2019

Bibliographical note

Funding Information:
We thank the Swanson Biotechnology Center at Koch Institute for assisting with NGS. TKL is supported by the Department of Defense (W81XWH-16-1-0565, W81XWH-18-1-0513), the Defense Advanced Research Projects Agency, MIT Portugal Program, and the Koch Institute Bridge Project. TKL and YT are supported by the United States-Israel Binational Science Foundation (#2017189) and YT is supported by the Israel Cancer Association (#0394837). SDR is supported in part by the NIH (R01 CA160762). MW is supported by the Department of Defense (W81XWH-16-1-0452). EMN was supported by an HFSP long-term post-doctoral fellowship (LT000307/2013-L).

Publisher Copyright:
© 2019, The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-019-10912-8

Cite this

Wu, M. R., Nissim, L., Stupp, D., Pery, E., Binder-Nissim, A., Weisinger, K., Enghuus, C., Palacios, S. R., Humphrey, M., Zhang, Z., Maria Novoa, E., Kellis, M., Weiss, R., Rabkin, S. D., Tabach, Y., & Lu, T. K. (2019). A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS). Nature Communications, 10(1), Article 2880. https://doi.org/10.1038/s41467-019-10912-8

@article{0b0ba852ec09496484e3cc54b43f8468,

title = "A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)",

abstract = "Cell state-specific promoters constitute essential tools for basic research and biotechnology because they activate gene expression only under certain biological conditions. Synthetic Promoters with Enhanced Cell-State Specificity (SPECS) can be superior to native ones, but the design of such promoters is challenging and frequently requires gene regulation or transcriptome knowledge that is not readily available. Here, to overcome this challenge, we use a next-generation sequencing approach combined with machine learning to screen a synthetic promoter library with 6107 designs for high-performance SPECS for potentially any cell state. We demonstrate the identification of multiple SPECS that exhibit distinct spatiotemporal activity during the programmed differentiation of induced pluripotent stem cells (iPSCs), as well as SPECS for breast cancer and glioblastoma stem-like cells. We anticipate that this approach could be used to create SPECS for gene therapies that are activated in specific cell states, as well as to study natural transcriptional regulatory networks.",

author = "Wu, {Ming Ru} and Lior Nissim and Doron Stupp and Erez Pery and Adina Binder-Nissim and Karen Weisinger and Casper Enghuus and Palacios, {Sebastian R.} and Melissa Humphrey and Zhizhuo Zhang and {Maria Novoa}, Eva and Manolis Kellis and Ron Weiss and Rabkin, {Samuel D.} and Yuval Tabach and Lu, {Timothy K.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10912-8",

language = "אנגלית",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Wu, MR, Nissim, L, Stupp, D, Pery, E, Binder-Nissim, A, Weisinger, K, Enghuus, C, Palacios, SR, Humphrey, M, Zhang, Z, Maria Novoa, E, Kellis, M, Weiss, R, Rabkin, SD, Tabach, Y & Lu, TK 2019, 'A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)', Nature Communications, vol. 10, no. 1, 2880. https://doi.org/10.1038/s41467-019-10912-8

TY - JOUR

T1 - A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)

AU - Wu, Ming Ru

AU - Nissim, Lior

AU - Stupp, Doron

AU - Pery, Erez

AU - Binder-Nissim, Adina

AU - Weisinger, Karen

AU - Enghuus, Casper

AU - Palacios, Sebastian R.

AU - Humphrey, Melissa

AU - Zhang, Zhizhuo

AU - Maria Novoa, Eva

AU - Kellis, Manolis

AU - Weiss, Ron

AU - Rabkin, Samuel D.

AU - Tabach, Yuval

AU - Lu, Timothy K.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Cell state-specific promoters constitute essential tools for basic research and biotechnology because they activate gene expression only under certain biological conditions. Synthetic Promoters with Enhanced Cell-State Specificity (SPECS) can be superior to native ones, but the design of such promoters is challenging and frequently requires gene regulation or transcriptome knowledge that is not readily available. Here, to overcome this challenge, we use a next-generation sequencing approach combined with machine learning to screen a synthetic promoter library with 6107 designs for high-performance SPECS for potentially any cell state. We demonstrate the identification of multiple SPECS that exhibit distinct spatiotemporal activity during the programmed differentiation of induced pluripotent stem cells (iPSCs), as well as SPECS for breast cancer and glioblastoma stem-like cells. We anticipate that this approach could be used to create SPECS for gene therapies that are activated in specific cell states, as well as to study natural transcriptional regulatory networks.

AB - Cell state-specific promoters constitute essential tools for basic research and biotechnology because they activate gene expression only under certain biological conditions. Synthetic Promoters with Enhanced Cell-State Specificity (SPECS) can be superior to native ones, but the design of such promoters is challenging and frequently requires gene regulation or transcriptome knowledge that is not readily available. Here, to overcome this challenge, we use a next-generation sequencing approach combined with machine learning to screen a synthetic promoter library with 6107 designs for high-performance SPECS for potentially any cell state. We demonstrate the identification of multiple SPECS that exhibit distinct spatiotemporal activity during the programmed differentiation of induced pluripotent stem cells (iPSCs), as well as SPECS for breast cancer and glioblastoma stem-like cells. We anticipate that this approach could be used to create SPECS for gene therapies that are activated in specific cell states, as well as to study natural transcriptional regulatory networks.

UR - http://www.scopus.com/inward/record.url?scp=85068221603&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-10912-8

DO - 10.1038/s41467-019-10912-8

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 31253799

AN - SCOPUS:85068221603

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2880

ER -

A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS)

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this