Combining transcriptional profiling and genetic linkage analysis to uncover gene networks operating in hematopoietic stem cells and their progeny

Abstract

Stem cells are unique in that they possess both the capacity to self-renew and thereby maintain their original pool as well as the capacity to differentiate into mature cells. In the past number of years, transcriptional profiling of enriched stem cell populations has been extensively performed in an attempt to identify a universal stem cell gene expression signature. While stem-cellspecific transcripts were identified in each case, this approach has thus far been insufficient to identify a universal group of core "stemness" genes ultimately responsible for self-renewal and multipotency. Similarly, in the hematopoietic system, comparisons of transcriptional profiles between different hematopoietic cell stages have had limited success in revealing core genes ultimately responsible for the initiation of differentiation and lineage specification. Here, we propose that the combined use of transcriptional profiling and genetic linkage analysis, an approach called "genetical genomics", can be a valuable tool to assist in the identification of genes and gene networks that specify "stemness" and cell fate decisions. We review past studies of hematopoietic cells that utilized transcriptional profiling and/or genetic linkage analysis, and discuss several potential future applications of genetical genomics.

Genetic screen identifies microRNA cluster 99b/let-7e/125a as a regulator of primitive hematopoietic cells

“…The size of the sectors in the pie chart was defined based on the number of genes assigned to the category (in redundant fashion). Genes not assigned to any of the defined categories [1][2][3][4][5][6][7] were defined as Other. 8 Gene Ontology analyses were performed using GOAL software.…”

“…Yet, we were not able to identify any published HSPC traits that mapped to the here-reported locus containing miR-cluster 99b/let7e/125a. 7 We anticipate that future genetic studies will shed new light on how microRNAs modulate HSPC fate and on how they themselves are regulated.…”

“…5,6 Each of these strains represents a unique, but stable, genetic mosaic of B6 and D2 alleles. By making use of these strains, variation in many different HSPC traits has been mapped to genomic regions (reviewed in Gerrits et al 7 ). Previously, we analyzed mRNA expression variation in developmentally related cell types isolated from the BXD mouse panel.…”

Characterization and Classification of Stem Cells

“…Later on, a third independent expression pro fi ling study (Fortunel et al 2003 ) reduced the list of commonly expressed genes to just one: integrin alpha-6. Thus, a universal stem cell signature may not exist, but each stem cell type may have its own transcriptional network responsible for certain unique stem cell properties (Gerrits et al 2008 ) . A comprehensive transcriptome analysis of human hematopoiesis was recently carried out by Novershtern et al ( 2011 ) and revealed dense transcriptional circuits in HSCs, that gradually disappear during differentiation, while new but less intricate circuits emerge.…”

Characterization of the genetic and environmental factors driving gene expression variability

“…Perturbations across multiple regulatory genes in a network can have a much a larger effect on disease than single gene changes [234]. Analysis of variants affecting gene networks has elucidated interesting processes with regards to complex diseases such as obesity [46], regulatory networks in stem cells [235] and immune response [236]. Analyzing systems affected by mutations can also give biological insight into the function of identified eQTLs and can even identify novel functions.…”