Revisiting the Central Dogma of Molecular Biology at the Genome Scale and in Single Cells

The central dogma of molecular biology, a term coined by Francis Crick in 1958, is the foundation of modern molecular biology. The central dogma describes how genetic information is transcribed to messenger RNAs and expressed to produce proteins that form the building blocks of a living cell and fulfill all biological functions. The central dogma of molecular biology is also called a DNA-RNA-protein axis.

However, it turns out the correlation between DNA copy number variation, mRNA expression level, and the production of specific proteins is very poor, which is quite puzzling and represents a major challenge to accurate prediction of cell fate and function from genetic information, one of the main goals of Genomic Medicine. This is due in part to the following reasons: First, there exists a complex gene-gene interaction network controlled by a range of epigenetic switches, suggesting the need for examining all genes at the same time as well as the regulatory elements at the genome scale. Second, non-genetic heterogeneity of single cells and stochastic fluctuation of RNAs and proteins, which indicates the need for high-throughput analysis in single cells. Despite recent advances in DNA sequencing technologies, it is still challenging to investigate the information flow through all the levels of the central dogma of molecular biology (DNA to RNA to protein) across the whole genome and in single cells.

The research at Yale University aims to develop an integrated microsystem that can manipulate single cells, extract and process genomic DNA, mRNAs and cytoplasmic proteins from the same cell, and subsequently perform whole pool amplification. In conjunction with the next-gene sequencing, it can enable us to conduct genome-scale, multi-level (genomic, epigenomic, transcriptomic and functional proteomic, or even phenotypic) analysis of single cells. Yale University is applying this platform to the study of single tumor cells from hematologic cancer patients in order to dissect the clonal evolution of cancer cells as well as reveal the underlying mechanisms that drive the development of such a heterogeneous malignancy in human.

Cell heterogeneity – a result of the genetic diversity present within the central dogma of molecular biology – plays a central role during normal development and in disease states. To study the genomic and transcriptome differences between cell population and even single cells you have to overcome the first main limiting factor which is the amount of starting material. Amplification of starting material is essential to perform analysis of genome and transcriptome of single cells.

Join this webinar to revisit the central dogma of molecular biology, learn more about single-cell DNA-RNA co-analysis, and cell heterogeneity.

Speakers

Rong Fan, Ph.D., Associate Professor of Biomedical Engineering, Yale University

Rong Fan is Associate Professor of Biomedical Engineering. He received his Ph.D. in Chemistry from the University of California at Berkeley in 2006 where his research was focused on nanomaterials for energy conversion and ion transport in nanofluidic systems. After completing his doctorate he joined the NanoSystems Biology Cancer Center at Caltech as a postdoctoral associate working in Prof. James Heath’s group where he began to explore the opportunities of applying microsystems to precision cancer research. In 2010, he started his own laboratory in Department of Biomedical Engineering at Yale University. His recent work has been focused on the development of an array of single-cell analysis technologies and then the utilization of systems biology principles to investigate cellular heterogeneity in human cancers and the immune system. He is the recipient of numerous awards including the Howard Temin Pathway to Independence award (K99/R00) from National Cancer Institute, the NSF Early Stage Faculty Career Development (CAREER) Award and the Packard Fellowship for Science and Engineering.

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Ioanna Andreou, Ph.D., Senior Scientist, QIAGEN

Dr. Ioanna Andreou is a senior scientist at QIAGEN and is responsible for developing technologies for single cell analysis. Dr. Andreou received her Ph.D. from University of Freiburg. She has published extensively in the area of gene silencing and hold multiple patents in this field. She joined QIAGEN after a postdoctoral fellowship in University of Cologne in 2002, and has held multiple positions in R&D in the area of molecular diagnostics, modification and amplification.

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