[
{
"id": "authors:ptmsd-9g284",
"collection": "authors",
"collection_id": "ptmsd-9g284",
"cite_using_url": "https://authors.library.caltech.edu/records/ptmsd-9g284",
"type": "article",
"title": "The lives of cells, recorded",
"author": [
{
"family_name": "Askary",
"given_name": "Amjad",
"orcid": "0000-0002-2913-8498"
},
{
"family_name": "Chen",
"given_name": "Wei",
"orcid": "0000-0002-5255-4166"
},
{
"family_name": "Choi",
"given_name": "Junhong",
"orcid": "0000-0001-9291-5977"
},
{
"family_name": "Du",
"given_name": "Lucia Y.",
"orcid": "0000-0003-0151-3783"
},
{
"family_name": "Elowitz",
"given_name": "Michael B.",
"orcid": "0000-0002-1221-0967",
"clpid": "Elowitz-M-B"
},
{
"family_name": "Gagnon",
"given_name": "James A.",
"orcid": "0000-0003-3978-6058"
},
{
"family_name": "Schier",
"given_name": "Alexander F.",
"orcid": "0000-0001-7645-5325"
},
{
"family_name": "Seidel",
"given_name": "Sophie",
"orcid": "0000-0002-4484-9888"
},
{
"family_name": "Shendure",
"given_name": "Jay",
"orcid": "0000-0002-1516-1865"
},
{
"family_name": "Stadler",
"given_name": "Tanja",
"orcid": "0000-0001-6431-535X"
},
{
"family_name": "Tran",
"given_name": "Martin",
"orcid": "0000-0001-9882-7230",
"clpid": "Tran-Martin"
}
],
"abstract": "A paradigm for biology is emerging in which cells can be genetically programmed to write their histories into their own genomes. These records can subsequently be read, and the cellular histories reconstructed, which for each cell could include a record of its lineage relationships, extrinsic influences, internal states and physical locations, over time. DNA recording has the potential to transform the way that we study developmental and disease processes. Recent advances in genome engineering are driving the development of systems for DNA recording, and meanwhile single-cell and spatial omics technologies increasingly enable the recovery of the recorded information. Combined with advances in computational and phylogenetic inference algorithms, the DNA recording paradigm is beginning to bear fruit. In this Perspective, we explore the rationale and technical basis of DNA recording, what aspects of cellular biology might be recorded and how, and the types of discovery that we anticipate this paradigm will enable.",
"doi": "10.1038/s41576-024-00788-w",
"issn": "1471-0056",
"publisher": "Nature Publishing Group",
"publication": "Nature Reviews Genetics",
"publication_date": "2025-03",
"volume": "26",
"pages": "203\u2013222"
},
{
"id": "authors:bry5v-p1a17",
"collection": "authors",
"collection_id": "bry5v-p1a17",
"cite_using_url": "https://authors.library.caltech.edu/records/bry5v-p1a17",
"type": "article",
"title": "Diversity in Notch ligand-receptor signaling interactions",
"author": [
{
"family_name": "Kuintzle",
"given_name": "Rachael",
"orcid": "0000-0002-1035-4983",
"clpid": "Kuintzle-Rachael-Christine"
},
{
"family_name": "Santat",
"given_name": "Leah A",
"orcid": "0000-0003-0511-9740",
"clpid": "Santat-Leah-A"
},
{
"family_name": "Elowitz",
"given_name": "Michael B.",
"orcid": "0000-0002-1221-0967",
"clpid": "Elowitz-M-B"
}
],
"abstract": "The Notch signaling pathway uses families of ligands and receptors to transmit signals to nearby cells. These components are expressed in diverse combinations in different cell types, interact in a many-to-many fashion, both within the same cell (in cis) and between cells (in trans), and their interactions are modulated by Fringe glycosyltransferases. A fundamental question is how the strength of Notch signaling depends on which pathway components are expressed, at what levels, and in which cells. Here, we used a quantitative, bottom-up, cell-based approach to systematically characterize trans-activation, cis-inhibition, and cis-activation signaling efficiencies across a range of ligand and Fringe expression levels in Chinese hamster and mouse cell lines. Each ligand (Dll1, Dll4, Jag1, and Jag2) and receptor variant (Notch1 and Notch2) analyzed here exhibited a unique profile of interactions, Fringe dependence, and signaling outcomes. All four ligands were able to bind receptors in cis and in trans, and all ligands trans-activated both receptors, although Jag1-Notch1 signaling was substantially weaker than other ligand-receptor combinations. Cis-interactions were predominantly inhibitory, with the exception of the Dll1- and Dll4-Notch2 pairs, which exhibited cis-activation stronger than trans-activation. Lfng strengthened Delta-mediated trans-activation and weakened Jagged-mediated trans-activation for both receptors. Finally, cis-ligands showed diverse cis-inhibition strengths, which depended on the identity of the trans-ligand as well as the receptor. The map of receptor-ligand-Fringe interaction outcomes revealed here should help guide rational perturbation and control of the Notch pathway.",
"doi": "10.7554/elife.91422",
"issn": "2050-084X",
"publisher": "eLife Sciences Publications, Ltd",
"publication": "eLife",
"publication_date": "2025-01-03",
"volume": "12"
},
{
"id": "authors:wgy1x-2tf47",
"collection": "authors",
"collection_id": "wgy1x-2tf47",
"cite_using_url": "https://authors.library.caltech.edu/records/wgy1x-2tf47",
"type": "article",
"title": "Temporal BMP4 effects on mouse embryonic and extraembryonic development",
"author": [
{
"family_name": "Hadas",
"given_name": "Ron"
},
{
"family_name": "Rubinstein",
"given_name": "Hernan"
},
{
"family_name": "Mittnenzweig",
"given_name": "Markus"
},
{
"family_name": "Mayshar",
"given_name": "Yoav"
},
{
"family_name": "Ben-Yair",
"given_name": "Raz"
},
{
"family_name": "Cheng",
"given_name": "Saifeng"
},
{
"family_name": "Aguilera-Castrejon",
"given_name": "Alejandro",
"orcid": "0000-0002-1339-7778"
},
{
"family_name": "Reines",
"given_name": "Netta"
},
{
"family_name": "Orenbuch",
"given_name": "Ayelet-Hashahar"
},
{
"family_name": "Lifshitz",
"given_name": "Aviezer",
"orcid": "0000-0002-8458-9507"
},
{
"family_name": "Chen",
"given_name": "Dong-Yuan",
"orcid": "0000-0003-2179-2847",
"clpid": "Chen-Dong-Yuan"
},
{
"family_name": "Elowitz",
"given_name": "Michael B.",
"orcid": "0000-0002-1221-0967",
"clpid": "Elowitz-M-B"
},
{
"family_name": "Zernicka-Goetz",
"given_name": "Magdalena",
"orcid": "0000-0002-7004-2471",
"clpid": "Zernicka-Goetz-M"
},
{
"family_name": "Hanna",
"given_name": "Jacob H.",
"orcid": "0000-0003-2042-9974"
},
{
"family_name": "Tanay",
"given_name": "Amos",
"orcid": "0000-0001-9419-3824"
},
{
"family_name": "Stelzer",
"given_name": "Yonatan",
"orcid": "0000-0001-9207-1479"
}
],
"abstract": "The developing placenta, which in mice originates through the extraembryonic ectoderm (ExE), is essential for mammalian embryonic development. Yet unbiased characterization of the differentiation dynamics of the ExE and its interactions with the embryo proper remains incomplete. Here we develop a temporal single-cell model of mouse gastrulation that maps continuous and parallel differentiation in embryonic and extraembryonic lineages. This is matched with a three-way perturbation approach to target signalling from the embryo proper, the ExE alone, or both. We show that ExE specification involves early spatial and transcriptional bifurcation of uncommitted ectoplacental cone cells and chorion progenitors. Early BMP4 signalling from chorion progenitors is required for proper differentiation of uncommitted ectoplacental cone cells and later for their specification towards trophoblast giant cells. We also find biphasic regulation by BMP4 in the embryo. The early ExE-originating BMP4 signal is necessary for proper mesoendoderm bifurcation and for allantois and primordial germ cell specification. However, commencing at embryonic day 7.5, embryo-derived BMP4 restricts the primordial germ cell pool size by favouring differentiation of their extraembryonic mesoderm precursors towards an allantois fate. ExE and embryonic tissues are therefore entangled in time, space and signalling axes, highlighting the importance of their integrated understanding and modelling in vivo and in vitro.
",
"doi": "10.1038/s41586-024-07937-5",
"issn": "0028-0836",
"publisher": "Nature Publishing Group",
"publication": "Nature",
"publication_date": "2024-10-17",
"volume": "634",
"pages": "652\u2013661"
},
{
"id": "authors:1zb8r-5xa88",
"collection": "authors",
"collection_id": "1zb8r-5xa88",
"cite_using_url": "https://authors.library.caltech.edu/records/1zb8r-5xa88",
"type": "article",
"title": "Synthetic protein circuits for programmable control of mammalian cell death",
"author": [
{
"family_name": "Xia",
"given_name": "Shiyu",
"orcid": "0000-0001-9024-0689",
"clpid": "Xia-Shiyu"
},
{
"family_name": "Lu",
"given_name": "Andrew C.",
"clpid": "Lu-Andrew-C"
},
{
"family_name": "Tobin",
"given_name": "Victoria",
"orcid": "0000-0002-2195-639X",
"clpid": "Tobin-Victoria"
},
{
"family_name": "Luo",
"given_name": "Kaiwen",
"orcid": "0000-0002-1597-1219",
"clpid": "Luo-Kaiwen"
},
{
"family_name": "Moeller",
"given_name": "Lukas",
"orcid": "0000-0002-4375-8837",
"clpid": "Moeller-Lukas"
},
{
"family_name": "Shon",
"given_name": "D. Judy",
"orcid": "0000-0001-8379-6195",
"clpid": "Shon-D-Judy"
},
{
"family_name": "Du",
"given_name": "Rongrong",
"orcid": "0009-0003-4942-3020",
"clpid": "Du-Rongrong"
},
{
"family_name": "Linton",
"given_name": "James M.",
"orcid": "0009-0008-2626-1803",
"clpid": "Linton-James-M"
},
{
"family_name": "Sui",
"given_name": "Margaret",
"orcid": "0009-0004-4129-0902",
"clpid": "Sui-Margaret"
},
{
"family_name": "Horns",
"given_name": "Felix",
"orcid": "0000-0001-5872-5061",
"clpid": "Horns-Felix"
},
{
"family_name": "Elowitz",
"given_name": "Michael B.",
"orcid": "0000-0002-1221-0967",
"clpid": "Elowitz-M-B"
}
],
"abstract": "\n
\n
Natural cell death pathways such as apoptosis and pyroptosis play dual roles: they eliminate harmful cells and modulate the immune system by dampening or stimulating inflammation. Synthetic protein circuits capable of triggering specific death programs in target cells could similarly remove harmful cells while appropriately modulating immune responses. However, cells actively influence their death modes in response to natural signals, making it challenging to control death modes. Here, we introduce naturally inspired “synpoptosis” circuits that proteolytically regulate engineered executioner proteins and mammalian cell death. These circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. Furthermore, synpoptosis circuits can be transmitted intercellularly, offering a foundation for engineering synthetic killer cells that induce desired death programs in target cells without self-destruction. Together, these results lay the groundwork for programmable control of mammalian cell death.
\n
\n
\n
\n
In multicellular organisms, cell types must be produced and maintained in appropriate proportions. One way this is achieved is through committed progenitor cells or extrinsic interactions that produce specific patterns of descendant cell types on lineage trees. However, cell fate commitment is probabilistic in most contexts, making it difficult to infer these dynamics and understand how they establish overall cell type proportions. Here, we introduce Lineage Motif Analysis (LMA), a method that recursively identifies statistically overrepresented patterns of cell fates on lineage trees as potential signatures of committed progenitor states or extrinsic interactions. Applying LMA to published datasets reveals spatial and temporal organization of cell fate commitment in zebrafish and rat retina and early mouse embryonic development. Comparative analysis of vertebrate species suggests that lineage motifs facilitate adaptive evolutionary variation of retinal cell type proportions. LMA thus provides insight into complex developmental processes by decomposing them into simpler underlying modules.
\n
\n
\n
In animal cells, molecular pathways often comprise families of variant components, such as ligands or receptors. These pathway components are differentially expressed by different cell types, potentially tailoring pathway function to cell context. However, it has remained unclear how pathway expression profiles are distributed across cell types and whether similar profiles can occur in dissimilar cell types. Here, using single-cell gene expression datasets, we identified pathway expression motifs, defined as recurrent expression profiles that are broadly distributed across diverse cell types. Motifs appeared in core pathways, including TGF-β, Notch, Wnt, and the SRSF splice factors, and involved combinatorial co-expression of multiple components. Motif usage was weakly correlated between pathways in adult cell types and during dynamic developmental transitions. Together, these results suggest a mosaic view of cell type organization, in which different cell types operate many of the same pathways in distinct modes.
\n
Methylation of cytosines in CG dinucleotides (CpGs) within promoters has been shown to lead to gene silencing in mammals in natural contexts. Recently, engineered recruitment of methyltransferases (DNMTs) at specific loci was shown to be sufficient to silence synthetic and endogenous gene expression through this mechanism. A critical parameter for DNA methylation-based silencing is the distribution of CpGs within the target promoter. However, how the number or density of CpGs in the target promoter affects the dynamics of silencing by DNMT recruitment has remained unclear. Here, we constructed a library of promoters with systematically varying CpG content, and analyzed the rate of silencing in response to recruitment of DNMT. We observed a tight correlation between silencing rate and CpG content. Further, methylation-specific analysis revealed a constant accumulation rate of methylation at the promoter after DNMT recruitment. We identified a single CpG site between TATA box and transcription start site (TSS) that accounted for a substantial part of the difference in silencing rates between promoters with differing CpG content, indicating that certain residues play disproportionate roles in controlling silencing. Together, these results provide a library of promoters for synthetic epigenetic and gene regulation applications, as well as insights into the regulatory link between CpG content and silencing rate.
",
"doi": "10.1021/acssynbio.3c00078",
"pmcid": "PMC10510725",
"issn": "2161-5063",
"publisher": "American Chemical Society",
"publication": "ACS Synthetic Biology",
"publication_date": "2023-09-15",
"series_number": "9",
"volume": "12",
"issue": "9",
"pages": "2536-2545"
},
{
"id": "authors:5wh3x-cj477",
"collection": "authors",
"collection_id": "5wh3x-cj477",
"cite_using_url": "https://authors.library.caltech.edu/records/5wh3x-cj477",
"type": "article",
"title": "Engineering RNA export for measurement and manipulation of living cells",
"author": [
{
"family_name": "Horns",
"given_name": "Felix",
"orcid": "0000-0001-5872-5061",
"clpid": "Horns-Felix"
},
{
"family_name": "Martinez",
"given_name": "Joe A.",
"clpid": "Martniez-Joe-A"
},
{
"family_name": "Fan",
"given_name": "Chengcheng",
"orcid": "0000-0003-4213-5758",
"clpid": "Fan-Chengcheng"
},
{
"family_name": "Haque",
"given_name": "Mehernaz",
"clpid": "Haque-Mehernaz"
},
{
"family_name": "Linton",
"given_name": "James M.",
"clpid": "Linton-James-M"
},
{
"family_name": "Tobin",
"given_name": "Victoria",
"orcid": "0000-0002-2195-639X",
"clpid": "Tobin-Victoria-R"
},
{
"family_name": "Santat",
"given_name": "Leah",
"orcid": "0000-0003-0511-9740",
"clpid": "Santat-Leah"
},
{
"family_name": "Maggiolo",
"given_name": "Ailiena O.",
"orcid": "0000-0003-1707-5060",
"clpid": "Maggiolo-Ailiena-O"
},
{
"family_name": "Bjorkman",
"given_name": "Pamela J.",
"orcid": "0000-0002-2277-3990",
"clpid": "Bjorkman-P-J"
},
{
"family_name": "Lois",
"given_name": "Carlos",
"orcid": "0000-0002-7305-2317",
"clpid": "Lois-Carlos"
},
{
"family_name": "Elowitz",
"given_name": "Michael B.",
"orcid": "0000-0002-1221-0967",
"clpid": "Elowitz-M-B"
}
],
"abstract": "A system for programmable export of RNA molecules from living cells would enable both non-destructive monitoring of cell dynamics and engineering of cells capable of delivering executable RNA programs to other cells. We developed genetically encoded cellular RNA exporters, inspired by viruses, that efficiently and selectively package and secrete target RNA molecules from mammalian cells within protective nanoparticles. Exporting and sequencing RNA barcodes enabled non-destructive monitoring of cell population dynamics with clonal resolution. Further, by incorporating fusogens into the nanoparticles, we demonstrated delivery, expression, and functional activity of exported mRNA in recipient cells. We term these systems COURIER (Controlled Output and Uptake of RNA for Interrogation, Expression, and Regulation). COURIER enables measurement of cell dynamics and establishes a foundation for hybrid cell and gene therapies based on cell-to-cell delivery of RNA.
",
"doi": "10.1016/j.cell.2023.06.013",
"pmcid": "PMC10528933",
"issn": "0092-8674",
"publisher": "Cell Press",
"publication": "Cell",
"publication_date": "2023-08-17",
"series_number": "17",
"volume": "186",
"issue": "17",
"pages": "3642-3658.e32"
},
{
"id": "authors:hj8zd-08q75",
"collection": "authors",
"collection_id": "hj8zd-08q75",
"cite_using_url": "https://authors.library.caltech.edu/records/hj8zd-08q75",
"type": "article",
"title": "Reconstitution of morphogen shuttling circuits",
"author": [
{
"family_name": "Zhu",
"given_name": "Ronghui",
"orcid": "0000-0001-8171-482X",
"clpid": "Zhu-Ronghui"
},
{
"family_name": "Santat",
"given_name": "Leah A.",
"orcid": "0000-0003-0511-9740",
"clpid": "Santat-Leah-A"
},
{
"family_name": "Markson",
"given_name": "Joseph S.",
"orcid": "0000-0002-3167-3887",
"clpid": "Markson-Joseph-S"
},
{
"family_name": "Nandagopal",
"given_name": "Nagarajan",
"orcid": "0000-0002-0469-6549",
"clpid": "Nandagopal-Nagarajan"
},
{
"family_name": "Gregrowicz",
"given_name": "Jan",
"clpid": "Gregrowicz-Jan"
},
{
"family_name": "Elowitz",
"given_name": "Michael B.",
"orcid": "0000-0002-1221-0967",
"clpid": "Elowitz-M-B"
}
],
"abstract": "Developing tissues form spatial patterns by establishing concentration gradients of diffusible signaling proteins called morphogens. The bone morphogenetic protein (BMP) morphogen pathway uses a family of extracellular modulators to reshape signaling gradients by actively \"shuttling\" ligands to different locations. It has remained unclear what circuits are sufficient to enable shuttling, what other patterns they can generate, and whether shuttling is evolutionarily conserved. Here, using a synthetic, bottom-up approach, we compared the spatiotemporal dynamics of different extracellular circuits. Three proteins\u2014Chordin, Twsg, and the BMP-1 protease\u2014successfully displaced gradients by shuttling ligands away from the site of production. A mathematical model explained the different spatial dynamics of this and other circuits. Last, combining mammalian and\n Drosophila\n components in the same system suggests that shuttling is a conserved capability. Together, these results reveal principles through which extracellular circuits control the spatiotemporal dynamics of morphogen signaling.",
"doi": "10.1126/sciadv.adf9336",
"pmcid": "PMC10337948",
"issn": "2375-2548",
"publisher": "American Association for the Advancement of Science",
"publication": "Science Advances",
"publication_date": "2023-07-14",
"series_number": "28",
"volume": "9",
"issue": "28",
"pages": "eadf9336"
},
{
"id": "authors:chs4b-tpy53",
"collection": "authors",
"collection_id": "chs4b-tpy53",
"cite_using_url": "https://authors.library.caltech.edu/records/chs4b-tpy53",
"type": "article",
"title": "The computational capabilities of many-to-many protein interaction networks",
"author": [
{
"family_name": "Klumpe",
"given_name": "Heidi E.",
"orcid": "0000-0001-8938-2006",
"clpid": "Klumpe-Heidi-E"
},
{
"family_name": "Garcia-Ojalvo",
"given_name": "Jordi",
"orcid": "0000-0002-3716-7520",
"clpid": "Garcia-Ojalvo-Jordi"
},
{
"family_name": "Elowitz",
"given_name": "Michael B.",
"orcid": "0000-0002-1221-0967",
"clpid": "Elowitz-M-B"
},
{
"family_name": "Antebi",
"given_name": "Yaron E.",
"orcid": "0000-0002-5771-6814",
"clpid": "Antebi-Yaron-E"
}
],
"abstract": "\n
\n
Many biological circuits comprise sets of protein variants that interact with one another in a many-to-many, or promiscuous, fashion. These architectures can provide powerful computational capabilities that are especially critical in multicellular organisms. Understanding the principles of biochemical computations in these circuits could allow more precise cellular control of cellular behaviors. However, these systems are inherently difficult to analyze, due to their large number of interacting molecular components, partial redundancies, and cell context dependence. Here, we discuss recent experimental and theoretical advances that are beginning to reveal how promiscuous circuits compute, what roles those computations play in natural biological contexts, and how promiscuous architectures can be applied for the design of synthetic multicellular behaviors.
\n
\n