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Article: Principles of Computation by Competitive Protein Dimerization Networks.

Parres-Gold, Jacob / Levine, Matthew / Emert, Benjamin / Stuart, Andrew / Elowitz, Michael B

bioRxiv : the preprint server for biology

2023

Abstract: Many biological signaling pathways employ proteins that competitively dimerize in diverse combinations. These dimerization networks can perform biochemical computations, in which the concentrations of monomers (inputs) determine the concentrations of ... ...

Abstract	Many biological signaling pathways employ proteins that competitively dimerize in diverse combinations. These dimerization networks can perform biochemical computations, in which the concentrations of monomers (inputs) determine the concentrations of dimers (outputs). Despite their prevalence, little is known about the range of input-output computations that dimerization networks can perform (their "expressivity") and how it depends on network size and connectivity. Using a systematic computational approach, we demonstrate that even small dimerization networks (3-6 monomers) are
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.30.564854
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Article: 3D genome organization around nuclear speckles drives mRNA splicing efficiency.

Bhat, Prashant / Chow, Amy / Emert, Benjamin / Ettlin, Olivia / Quinodoz, Sofia A / Takei, Yodai / Huang, Wesley / Blanco, Mario R / Guttman, Mitchell

bioRxiv : the preprint server for biology

2023

Abstract: The nucleus is highly organized such that factors involved in transcription and processing of distinct classes of RNA are organized within specific nuclear bodies. One such nuclear body is the nuclear speckle, which is defined by high concentrations of ... ...

Abstract	The nucleus is highly organized such that factors involved in transcription and processing of distinct classes of RNA are organized within specific nuclear bodies. One such nuclear body is the nuclear speckle, which is defined by high concentrations of protein and non-coding RNA regulators of pre-mRNA splicing. What functional role, if any, speckles might play in the process of mRNA splicing remains unknown. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs, and higher co-transcriptional splicing levels relative to genes that are located farther from nuclear speckles. We show that directed recruitment of a pre-mRNA to nuclear speckles is sufficient to drive increased mRNA splicing levels. Finally, we show that gene organization around nuclear speckles is highly dynamic with differential localization between cell types corresponding to differences in Pol II occupancy. Together, our results integrate the longstanding observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a critical role for dynamic 3D spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.
Language	English
Publishing date	2023-01-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.04.522632
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Article ; Online: Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells.

Jain, Naveen / Goyal, Yogesh / Dunagin, Margaret C / Cote, Christopher J / Mellis, Ian A / Emert, Benjamin / Jiang, Connie L / Dardani, Ian P / Reffsin, Sam / Arnett, Miles / Yang, Wenli / Raj, Arjun

Cell systems

2024 Volume 15, Issue 2, Page(s) 109–133.e10

Abstract: Pluripotency can be induced in somatic cells by the expression of OCT4, KLF4, SOX2, and MYC. Usually only a rare subset of cells reprogram, and the molecular characteristics of this subset remain unknown. We apply retrospective clone tracing to identify ... ...

Abstract	Pluripotency can be induced in somatic cells by the expression of OCT4, KLF4, SOX2, and MYC. Usually only a rare subset of cells reprogram, and the molecular characteristics of this subset remain unknown. We apply retrospective clone tracing to identify and characterize the rare human fibroblasts primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis increased the reprogramming efficiency. We provide evidence for a unified model in which cells can move into and out of the primed state over time, explaining how reprogramming appears deterministic at short timescales and stochastic at long timescales. Furthermore, inhibiting the activity of LSD1 enlarged the pool of cells that were primed for reprogramming. Thus, even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.
MeSH term(s)	Humans ; Cellular Reprogramming ; Induced Pluripotent Stem Cells/metabolism ; Kruppel-Like Factor 4 ; Retrospective Studies ; Fibroblasts
Chemical Substances	Kruppel-Like Factor 4
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2024.01.001
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Article ; Online: Gene regulation gravitates toward either addition or multiplication when combining the effects of two signals.

Sanford, Eric M / Emert, Benjamin L / Coté, Allison / Raj, Arjun

eLife

2020 Volume 9

Abstract: Two different cell signals often affect transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. The most commonly used mechanistic models predict additive or ... ...

Abstract	Two different cell signals often affect transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. The most commonly used mechanistic models predict additive or multiplicative combined responses, but a systematic genome-wide evaluation of these predictions is not available. Here, we analyzed the transcriptional response of human MCF-7 cells to retinoic acid and TGF-β, applied individually and in combination. The combined transcriptional responses of induced genes exhibited a range of behaviors, but clearly favored both additive and multiplicative outcomes. We performed paired chromatin accessibility measurements and found that increases in accessibility were largely additive. There was some association between super-additivity of accessibility and multiplicative or super-multiplicative combined transcriptional responses, while sub-additivity of accessibility associated with additive transcriptional responses. Our findings suggest that mechanistic models of combined transcriptional regulation must be able to reproduce a range of behaviors.
MeSH term(s)	Chromatin/drug effects ; Chromatin/metabolism ; Gene Expression Regulation/drug effects ; Genes/drug effects ; Humans ; MCF-7 Cells/metabolism ; Smad Proteins/drug effects ; Smad Proteins/metabolism ; Transcription, Genetic/drug effects ; Transforming Growth Factor beta/pharmacology ; Tretinoin/pharmacology ; Up-Regulation
Chemical Substances	Chromatin ; Smad Proteins ; Transforming Growth Factor beta ; Tretinoin (5688UTC01R)
Language	English
Publishing date	2020-12-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.59388
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Article ; Online: Genome organization around nuclear speckles drives mRNA splicing efficiency.

Bhat, Prashant / Chow, Amy / Emert, Benjamin / Ettlin, Olivia / Quinodoz, Sofia A / Strehle, Mackenzie / Takei, Yodai / Burr, Alex / Goronzy, Isabel N / Chen, Allen W / Huang, Wesley / Ferrer, Jose Lorenzo M / Soehalim, Elizabeth / Goh, Say-Tar / Chari, Tara / Sullivan, Delaney K / Blanco, Mario R / Guttman, Mitchell

Nature

2024

Abstract: The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear ... ...

Abstract	The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies
Language	English
Publishing date	2024-05-08
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-024-07429-6
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Zs.MO 244: Show issues

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Article: Retrospective identification of intrinsic factors that mark pluripotency potential in rare somatic cells.

Jain, Naveen / Goyal, Yogesh / Dunagin, Margaret C / Cote, Christopher J / Mellis, Ian A / Emert, Benjamin / Jiang, Connie L / Dardani, Ian P / Reffsin, Sam / Raj, Arjun

bioRxiv : the preprint server for biology

2023

Abstract: Pluripotency can be induced in somatic cells by the expression of the four "Yamanaka" factors OCT4, KLF4, SOX2, and MYC. However, even in homogeneous conditions, usually only a rare subset of cells admit reprogramming, and the molecular characteristics ... ...

Abstract	Pluripotency can be induced in somatic cells by the expression of the four "Yamanaka" factors OCT4, KLF4, SOX2, and MYC. However, even in homogeneous conditions, usually only a rare subset of cells admit reprogramming, and the molecular characteristics of this subset remain unknown. Here, we apply retrospective clone tracing to identify and characterize the individual human fibroblast cells that are primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis led to increased reprogramming efficiency, identifying it as a barrier to reprogramming. Changing the frequency of reprogramming by inhibiting the activity of LSD1 led to an enlarging of the pool of cells that were primed for reprogramming. Our results show that even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.10.527870
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Article ; Online: Variability within rare cell states enables multiple paths toward drug resistance.

Emert, Benjamin L / Cote, Christopher J / Torre, Eduardo A / Dardani, Ian P / Jiang, Connie L / Jain, Naveen / Shaffer, Sydney M / Raj, Arjun

Nature biotechnology

2021 Volume 39, Issue 7, Page(s) 865–876

Abstract: Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining ... ...

Abstract	Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining precisely what variable molecular features lead to which cellular fates. Thus, we developed Rewind, a methodology that combines genetic barcoding with RNA fluorescence in situ hybridization to directly capture rare cells that give rise to cellular behaviors of interest. Applying Rewind to BRAF
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line ; Cell Survival/drug effects ; Drug Resistance, Neoplasm ; Extracellular Signal-Regulated MAP Kinases/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Integrin alpha3/genetics ; Integrin alpha3/metabolism ; Melanoma ; Phosphorylation ; Single-Cell Analysis ; Vemurafenib/pharmacology
Chemical Substances	Antineoplastic Agents ; ITGA3 protein, human ; Integrin alpha3 ; Vemurafenib (207SMY3FQT) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
Language	English
Publishing date	2021-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-021-00837-3
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 137: Show issues
Zs.MG 43: Show issues

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Article: Cell type determination for cardiac differentiation occurs soon after seeding of human-induced pluripotent stem cells

Jiang, Connie L. / Goyal, Yogesh / Jain, Naveen / Wang, Qiaohong / Truitt, Rachel E. / Coté, Allison J. / Emert, Benjamin / Mellis, Ian A. / Kiani, Karun / Yang, Wenli / Jain, Rajan / Raj, Arjun

Genome biology. 2022 Dec., v. 23, no. 1

2022

Abstract: BACKGROUND: Cardiac differentiation of human-induced pluripotent stem (hiPS) cells consistently produces a mixed population of cardiomyocytes and non-cardiac cell types, even when using well-characterized protocols. We sought to determine whether ... ...

Abstract	BACKGROUND: Cardiac differentiation of human-induced pluripotent stem (hiPS) cells consistently produces a mixed population of cardiomyocytes and non-cardiac cell types, even when using well-characterized protocols. We sought to determine whether different cell types might result from intrinsic differences in hiPS cells prior to the onset of differentiation. RESULTS: By associating individual differentiated cells that share a common hiPS cell precursor, we tested whether expression variability is predetermined from the hiPS cell state. In a single experiment, cells that shared a progenitor were more transcriptionally similar to each other than to other cells in the differentiated population. However, when the same hiPS cells were differentiated in parallel, we did not observe high transcriptional similarity across differentiations. Additionally, we found that substantial cell death occurs during differentiation in a manner that suggested all cells were equally likely to survive or die, suggesting that there is no intrinsic selection bias for cells descended from particular hiPS cell progenitors. We thus wondered how cells grow spatially during differentiation, so we labeled cells by expression of marker genes and found that cells expressing the same marker tended to occur in patches. Our results suggest that cell type determination across multiple cell types, once initiated, is maintained in a cell-autonomous manner for multiple divisions. CONCLUSIONS: Altogether, our results show that while substantial heterogeneity exists in the initial hiPS cell population, it is not responsible for the variability observed in differentiated outcomes; instead, factors specifying the various cell types likely act during a window that begins shortly after the seeding of hiPS cells for differentiation.
Keywords	cardiomyocytes ; cell death ; genome ; sowing ; transcription (genetics)
Language	English
Dates of publication	2022-12
Size	p. 90.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-022-02654-6
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Disrupting cellular memory to overcome drug resistance.

Harmange, Guillaume / Hueros, Raúl A Reyes / Schaff, Dylan L / Emert, Benjamin / Saint-Antoine, Michael / Kim, Laura C / Niu, Zijian / Nellore, Shivani / Fane, Mitchell E / Alicea, Gretchen M / Weeraratna, Ashani T / Simon, M Celeste / Singh, Abhyudai / Shaffer, Sydney M

Nature communications

2023 Volume 14, Issue 1, Page(s) 7130

Abstract: Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. ... ...

Abstract	Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. However, we lack robust methods to find regulators of memory or track state switching. Here, we develop a lineage tracing-based technique to quantify memory and identify cells that switch states. Applied to melanoma cells without therapy, we quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy. We also identify the PI3K and TGF-β pathways as state switching modulators. We propose a pretreatment model, first applying a PI3K inhibitor to modulate gene expression states, then applying targeted therapy, which leads to less resistance than targeted therapy alone. Together, we present a method for finding modulators of gene expression memory and their associated cell fates.
MeSH term(s)	Phosphatidylinositol 3-Kinases ; Cell Differentiation/genetics ; Drug Resistance, Neoplasm ; Transforming Growth Factor beta
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Transforming Growth Factor beta
Language	English
Publishing date	2023-11-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41811-8
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Article ; Online: ClampFISH 2.0 enables rapid, scalable amplified RNA detection in situ.

Dardani, Ian / Emert, Benjamin L / Goyal, Yogesh / Jiang, Connie L / Kaur, Amanpreet / Lee, Jasmine / Rouhanifard, Sara H / Alicea, Gretchen M / Fane, Mitchell E / Xiao, Min / Herlyn, Meenhard / Weeraratna, Ashani T / Raj, Arjun

Nature methods

2022 Volume 19, Issue 11, Page(s) 1403–1410

Abstract: RNA labeling in situ has enormous potential to visualize transcripts and quantify their levels in single cells, but it remains challenging to produce high levels of signal while also enabling multiplexed detection of multiple RNA species simultaneously. ... ...

Abstract	RNA labeling in situ has enormous potential to visualize transcripts and quantify their levels in single cells, but it remains challenging to produce high levels of signal while also enabling multiplexed detection of multiple RNA species simultaneously. Here, we describe clampFISH 2.0, a method that uses an inverted padlock design to efficiently detect many RNA species and exponentially amplify their signals at once, while also reducing the time and cost compared with the prior clampFISH method. We leverage the increased throughput afforded by multiplexed signal amplification and sequential detection to detect 10 different RNA species in more than 1 million cells. We also show that clampFISH 2.0 works in tissue sections. We expect that the advantages offered by clampFISH 2.0 will enable many applications in spatial transcriptomics.
MeSH term(s)	RNA/genetics ; Transcriptome
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-022-01653-6
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