Defining cell type with chromatin profiling

Developers

M Ryan Corces, Jason D Buenrostro, Ravindra Majeti, Howard Y Chang, etc.

Description of the technology

We define the chromatin accessibility. It allowed to determine transcriptional landscapes in 13 human primary blood cell types that span the hematopoietic hierarchy. Exploiting the finding that the enhancer landscape better reflects cell identity than mRNA levels, the developers of the technology proposed 'enhancer cytometry' for enumeration of pure cell types from complex populations. Regulators, governing hematopoietic differentiation were identified and further the lineage ontogeny of genetic elements linked to diverse human diseases was shown.

In acute myeloid leukemia (AML), chromatin accessibility uncovers unique regulatory evolution in cancer cells with a progressively increasing mutation burden. Single AML cells exhibit distinctive mixed regulome profiles corresponding to different developmental stages. A method to account for this regulatory heterogeneity was proposed. It identified cancer-specific deviations and HOX factors, implicated as key regulators of preleukemic hematopoietic stem cell characteristics. Thus, regulome dynamics can provide diverse insights into hematopoietic development and disease.

Practical application

The methodologies, proposed by this technology and used to study AML, can be valuable for the investigations of other blood and solid tumor malignancies. Probably, the regulatory heterogeneity is a widespread phenomenon in many types of cancer. That is why integrative approach of this technology and enhancer cytometry can be useful to construct synthetic normal cell analogs, which could be broadly applicable to many pathologies.

Technique of enhancer cytometry will help to understand a specificity of regulatory networks in the cases of various forms of cancer and reveal the aberrations that drive the formation and persistence of malignant disease. Thus, this technology provides a methodological basis for the mapping of regulomes of normal tissues to better understand the ontogeny of human diseases.

Laboratories

• Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford (USA)
• Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford (USA)
• Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford (USA)

Links

Publications

• Corces, M.R. et al. «Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution." 48.10 Nat Genet. (2016): 1193−1203.
• Spivakov, M. Fraser, P. «Defining cell type with chromatin profiling." 34.11 Nature Biotechnology, (2016): 1126–1128.
• Buenrostro, J.D. et al. «Single-cell chromatin accessibility reveals principles of regulatory variation." 523 Nature, (2015): 486−490.