RT Journal Article
SR Electronic
T1 Searching for the chromatin determinants of human hematopoiesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 082917
DO 10.1101/082917
A1 Enrique Carrillo-de-Santa-Pau
A1 David Juan
A1 Vera Pancaldi
A1 Felipe Were
A1 Ignacio Martin-Subero
A1 Daniel Rico
A1 Alfonso Valencia
A1 in behalf of The BLUEPRINT Consortium
YR 2016
UL http://biorxiv.org/content/early/2016/10/24/082917.abstract
AB Hematopoiesis is one of the best characterized biological systems but the connection between chromatin changes and lineage differentiation is not yet well understood. We have developed a bioinformatic workflow to generate a chromatin space that allows to classify forty-two human healthy blood epigenomes from the BLUEPRINT, NIH ROADMAP and ENCODE consortia by their cell type. This approach recapitulates the human hematopoietic differentiation tree model from an epigenomic perspective. The analysis of the orthogonal dimension of the chromatin space allows us to identify 32,662 chromatin determinant regions (CDRs), genomic regions with different epigenetic characteristics between the cell types. Functional analysis revealed that these regions are linked with cell identities. The inclusion of leukemia epigenomes in the healthy hematological chromatin sample space gives us insights on the origin of these tumors. Our method provides an analytical approach to study the relationship between epigenomic changes and cell lineage differentiation.Author summary The changes in the chromatin configuration, or epigenome, have an essential role in development and differentiation of cells, but how these epigenomic changes are connected with the different cell phenotypes is not well understood. Hematopoiesis is a dynamic process in which hematopoietic stem cells give rise many different cell types, including lymphocytes, neutrophils, monocytes, platelets or erythrocytes. Here we propose a computational approach to derive an epigenomic space from epigenomes representing multiple different cell types and describe its usefulness in the context of hematopoiesis. Concomitantly, our method recovers those genomic regions that are more informative about the segregation in different cell types. These regions are called Chromatin Determinant Regions (CDRs) as they present differential epigenetic states among different cell types. Further characterization of the detected hematopoietic CDRs shows that these genomic regions are associated to hematopoietic transcription factors and the expected functions that characterize each cell type. CDRs provide a valuable reference for the study of normal hematopoiesis as they allow to study epigenetic differences in the context of the whole system. Similarly, they help to explore the epigenomic differences of hematologic malignancies to the healthy cell types, providing additional clues about their cell of origin and about those epigenomic alterations interfering in normal hematopoiesis. Our approach will enable the integration of data from several resources for characterizing and comparing different differentiation systems when more data will be available.