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Stem Cell Genomics: Developmental Competence 

Stem Cell Genomics: Developmental Competence
Stem Cell Genomics: Developmental Competence

Kyle M. Loh

, Bing Lim

, and Lay Teng Ang

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date: 29 May 2020

Historically, developmental lineage tracing and grafting experiments have classically delineated the progenitor-progeny relationships which form the developmental hierarchies we know today, with various stem cell and progenitor lineages positioned at different levels. These findings laid the foundation of developmental biology but were previously confined to phenomenological descriptions of various progenitor-progeny relationships. Understanding the causal drivers of each discrete cell-fate transition within complex developmental hierarchies remains the overarching challenge of modern developmental biology: this is an issue that is optimally addressed by genomics approaches. Historically, regulatory genes behind particular lineage transitions were identified by genome-wide mutagenesis in model organisms (forward genetics) or genetic ablation of selected candidate regulators (reverse genetics). These incredibly informative yet time-consuming approaches may yet be superseded by studies empowered by computational inference. For particular developmental hierarchies, for example the hematopoietic system, we now have accurate transcriptional profiles of rather pure populations of major stem cell populations, their progeny and the intermediates spanning between them. Therefore, we can make informed guesses of the regulatory genes that drive various lineage transitions by comparing differentially expressed genes that differ between proximal developmental intermediates and can narrow the list of regulatory genes to functionally test by gain- or loss-of-function analyses. Even in cell-fate relationships in which knowledge of key drivers was previously known, historically it has been difficult to ascribe exact molecular functions to these regulatory genes. However, ablation of known regulators followed by genome-wide transcriptional profiling can reveal the exact genes that are functionally invoked or repressed by them. ChIP-seq and related technologies can ascertain which genes are under the direct control of specific transcription factors or chromatin remodelers. In coming years, it will be necessary to employ descriptive genomics profiling with functional genetic approaches in equal measure. For example, it was previously extrapolated that pluripotency factors unilaterally inhibit differentiation, because pluripotency factors were found to occupy the promoters of many differentiation genes in ESCs via ChIP analyses. Nevertheless, only phenotypic gain- and loss-of-function approaches later uncovered that pluripotency factors actually upregulate a subset of these developmental genes and therefore specify ESC differentiation to particular lineage. Transcription factor binding identified by computational approaches cannot be inferred to mean either gene upregulation or downregulation and therefore we must seek, in both stem cell biology and developmental biology, to rigorously functionally validate all computational predictions. This review has emphasized the historic concept of developmental competence, conceptualized seventy years ago and the application of genomics to uncover the underlying mechanisms. However, our knowledge of its molecular foundation still remains fragmentary. We have proposed that lineage-specifying transcription factors within uncommitted stem cells capacitate specific lineage options, therefore providing a possible explanation for multilineage competence. Yet, the mechanistic details of how transcription factors “prime” developmental genes within undifferentiated stem cells remain unclear, although pioneer factor activity and corresponding chromatin accessibility at regulatory elements may be a parsimonious answer. At one end of the question, we have incomplete knowledge of the mechanistic workings of competence, and at the other extreme, even the basic definition of developmental competence has become increasingly vague, as stem cells and progenitors can apparently traverse lineage boundaries during injury and appreciably expand their lineage potential.

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