Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thus maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, we developed a lineage-tracing technology termed Barcode-decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree in a time-resolved manner whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. Herein we show that cell transcriptome states are both inherited and dynamically reshaped following constrained rules encoded within the cell lineage, leading to intra-clonal non-genetic diversity in basal growth conditions and while adjusting populational phenotypic output upon oncogene activation and throughout the process of reversible resistance to therapeutic cues.
Project description:Developmental origins of dendritic cells (DCs) including conventional DCs (cDCs, comprising cDC1 and cDC2 subsets) and plasmacytoid DCs (pDCs) remain unclear. We studied DC development in unmanipulated adult mice using inducible lineage tracing combined with clonal DNA "barcoding" and single-cell transcriptome and phenotype analysis (CITE-Seq). Inducible tracing of Cx3cr1+ hematopoietic progenitors in the bone marrow showed that they simultaneously produce all DC subsets including pDCs, cDC1s and cDC2s. Clonal tracing of hematopoietic stem cells (HSCs) and of Cx3cr1+ progenitors revealed clone sharing between cDC1s and pDCs, but not between the two cDC subsets or between pDCs and B cells. Accordingly, CITE-Seq analyses of differentiating HSCs and Cx3cr1+ progenitors identified progressive stages of pDC development including Cx3cr1+ Ly-6D+ propDCs that were distinct from lymphoid progenitors. These results reveal the shared origin of pDCs and cDCs, and suggest a revised scheme of DC development whereby pDCs share clonal relationship with cDC1s
Project description:We have assessed clonal heterogeneity within individual primary tumours and metastasis and also during the distinct stages of malignant tumour progression using the Confetti lineage reporter in the background of the MMTV-PyMT mouse model of metastatic breast cancer. Comparative gene expression analysis of the clonal populations reveals a substantial level of heterogeneity across and also within the various stages of breast carcinogenesis. This intra-stage heterogeneity is manifested by differences in cell proliferation, where the fast-proliferating subclass is further enriched in oxidative phosphorylation and cell death.