Baltimore, MD, USA. Scientists have produced the very first epigenetic landscape map for tissue differentiation, based on the occurrence of a common chemical change called methylation, often is associated with turning off genes. It takes place while stem cells decide their fates and progress from precursor to progeny, presenting an important key to undersanding cellular development..

The researchers, from Johns Hopkins, Stanford, and Harvard, focused on this epigenetic mark because it is found in one of the building blocks of DNA, and remembered by a cell when it divides. The team chose the blood cell system as its model because it's well-understood in terms of cellular development.

They looked at eight types of cells in various stages of commitment, including very early blood stem cells that had yet to differentiate into red and white blood cells. Employing a customized genome-wide methylation-profiling method dubbed CHARM (comprehensive high-throughput arrays for relative methylation), the team analyzed 4.6 million potentially methylated sites in a variety of blood cells from mice to see where DNA methylation changes occurred during the normal differentiation process.

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Epigenetic Maps

A new type of map visualizes biological inheritance in humans that is not based on DNA sequencing. Work underway indicates that as many as one in six human genes might be subject to modifications that could alter their activity under the influence of the physical environment. Such epigenetic changes include modification of DNA bases through the addition or removal of simple chemical tags and similar protein changes. These modifications, the epigenetic code, defines for many researchers how different genetic configurations can be executed from the same genome in different tissues with different results. Understanding these processes have become important in studies of human development, variation, and disease. Andrew Feinberg is a professor of medicine and molecular biology and genetics. In this video, he discusses epigenetic mapping and how changes outside the DNA sequence known as epigenetic changes can affect cell behavior.

Video courtesy of Johns Hopkins University. Time: 00:03:34.

The research team also looked at cells that are more committed to differentiation: the precursors of the two major types of white blood cells, lymphocytes and myeloid cells. Finally, they looked at older cells that were close to their ultimate fates to get more complete pictures of the precursor-progeny relationships — for example, at white blood cells that had gone fairly far in T-cell lymphocyte development. (Lymphoid and myeloid constitute the two major types of progenitor blood cells.)

Andrew Feinberg
Professor
Molecular Medicine

The project was a collaborative study between the Johns Hopkins University, Stanford University, and Harvard University. The findings appear in the journal Nature.

"It wasn't a complete tree, but it was large portions of the tree, and different branches," says Andrew Feinberg, M.D., M.P.H.

Feinberg is the King Fahd Professor of Molecular Medicine and director of the Center for Epigenetics at Hopkins' Institute for Basic Biomedical Sciences.

"Genes themselves aren't going to tell us what's really responsible for the great diversity in cell types in a complex organism like ourselves," Feinberg says. "But I think epigenetics—and how it controls genes-can."

"That's why we wanted to know what was happening generally to the levels of DNA methylation as cells differentiate."

One of the surprising finds was how widely DNA methylation patterns vary in cells as they differentiate. "It wasn't a boring linear process," Feinberg says. "Instead, we saw these waves of change during the development of these cell types."

The data shows that when all is said and done, the lymphocytes had many more methylated genes than myeloid cells. However, on the way to becoming highly methylated, lymphocytes experience a huge wave of loss of DNA methylation early in development and then a regain of methylation. The myeloid cells, on the other hand, undergo a wave of increased methylation early in development and then erase that methylation later in development.

Irving Weissman
Professor
Developmental Biology

Rudimentary as it is, this first epigenetic landscape map has predictive power in the reverse direction, according to Feinberg. The team could tell which types of stem cells the blood cells had come from, because epigenetically those blood cells had not fully let go of their past; they had residual marks that were characteristic of their lineage.

This project involved a repertoire of talents.."None of whom were more integral than Irv Weissman at Stanford," Feinberg says. "He's a great stem cell biologist and he lent a whole level of expertise that we didn't have."

One apparent application of this work might be to employ these same techniques to assess how completely an induced pluripotent stem cell (iPSC) has been reprogrammed. "You might want to have an incompletely reprogrammed cell type from blood, for example, that you take just to a certain point because then you want to turn it into a different kind of blood cell," Feinberg says, but cautions that the various applications are strictly theoretical at this time. Because the data seemed to indicate that discreet stages of cell differentiation are characterized by waves of changes in one direction and subsequent waves in another, cell types conceivably could be redefined according to epigenetic marks that will provide new insights into normal development, variation, and disease processes.

"Leukemias and lymphomas likely involve disruptions of the epigenetic landscape," Feinberg says. "As epigenetic maps such as this one begin to get fleshed out by us and others, they will guide our understanding of why those diseases behave the way they do, and pave the way for new therapies."

CitationEpigenetic memory in induced pluripotent stem cells. K. Kim, A. Doi, B. Wen, K. Ng, R. Zhao, P. Cahan, J. Kim, M. J. Aryee, H. Ji, L. I. R. Ehrlich, A. Yabuuchi, A. Takeuchi, K. C. Cunniff, H. Hongguang, S. Mckinney-Freeman, O. Naveiras, T. J. Yoon, R. A. Irizarry, N. Jung, J. Seita, J. Hanna, P. Murakami, R. Jaenisch, R. Weissleder, S. H. Orkin, I. L. Weissman, A. P. Feinberg and G. Q. Daley. Nature 2010; doi:10.1038/nature09342

Abstract

Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an ‘epigenetic memory’ of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.

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