How do blood cells develop? What causes a stem cell in bone marrow to become a specialized blood cell? A team of researchers, including Andrew Feinberg and Irving Weissman, is in the process of developing an epigenetic map of blood cell differentiation to help answer these questions.
To get the right blood cell type, start with a hematopoietic stem cell. This is a cell that can become any type of blood cell — from ordinary oxygen-carrying red blood cells to the specialized cells of the immune system — by following the right developmental pathway.
There are a number of different pathways, one for every type of blood cell, but they all start by differentiation into one of two types called lymphoid and myeloid. Lymphoid cells become the lymphocytes, a class of white blood cells. Myeloid cells become myelocytes (a separate class of white blood cells), erythrocytes (red blood cells) or other types of white blood cells.
These pathways involve the selective activation of specific genes in the DNA sequence. The right genes must be activated at the right time. However, Feinberg said, “It’s been thought since the 1930s that there must be some cellular memory that underlies stages of differentiation, but no such map had ever been made.” Epigenetics may help track the methods of selective gene expression during hematopoiesis.
Epigenetics involves modifying genes without affecting the sequence of DNA itself, so that only certain genes are activated. One common modification is called DNA methylation, in which a methane group is attached to the active site of a base in the genetic code — the location where the process of translating genes into the proteins used throughout the body begins.
An epigenetic map, like the map of the human genome before it, would help establish how our DNA gets processed — how it makes all the various cells that make up a person.
“We wanted to map the epigenetic landscape in a normal model of cellular differentiation, hematopoiesis,” Feinberg said.
Hematopoiesis is the process by which the various types of blood cells develop. A map of the epigenetics of hematopoiesis could prove useful in understanding how blood cells are made in the body. It could also help increase our understanding of potential dysfunctions in blood cell development.
There were two main steps involved. “We purified mouse blood cells at each stage of development, from blood-forming stem cells to blood cells,” Weissman said. These purified cells were then sent to Feinberg’s lab, where the epigenetic patterns were analyzed.
“Andy Feinberg and his group had developed a large scale method to examine chromosomal DNA modifications that determine or are determined by whether a gene is expressed or not,” Weissman said. Scientists have already determined which genes are expressed at each stage of cell development; the issue was how epigenetic modifications to the DNA sequence could trigger the selective expression of the right gene at the right time.
Feinberg’s analysis allowed him to develop a map of the ‘epigenome’ — the patterns of methylation and demethylation of DNA that take place during hematopoiesis. These patterns are, like so much in the body, complex: During differentiation, both increases and decreases were observed, changing over time. However, Feinberg said, “We found a marked difference between lymphocytes and myelocytes, with the lymphocytes more methylated.”
Generally, there was a distinct pattern to where in the DNA changes occurred. According to Weissman, “the chromosomal changes occurred in large ‘islands’ of DNA, and also ‘shores’ not too far away from the islands. The changes in the shores look most interesting for cell fate decisions.”
“Many new genes involved in hematopoiesis were found in this process as well, including some that could modify epigenetic change itself,” Feinberg said.
These new genes, along with the epigenetic map, will help contribute to our understanding of cell development.
