Dr. Lindsay Shopland Investigates 3D Chromosome Architecture
JAX® NOTES Issue 509, Spring 2008
Jackson Laboratory Assistant Professor Lindsay Shopland PhD was first inspired to study science by her 9th grade biology teacher, who encouraged her to participate in an outreach program for high school students at Columbia University. At Columbia, she was exposed to computer programming, molecular, and cancer biology, which led her to decide to major in biology at Bucknell University, Lewisburg, PA.
After graduating from Bucknell, she earned a PhD in biochemistry from Cornell University, Ithaca, NY. She followed this with a postdoctoral fellowship at University of Massachusetts Medical School, Worcester. There, Dr. Shopland found a mentor in Dr. Jeanne Lawrence, one of the pioneers in nuclear and chromosome structure research. Now a research scientist at The Jackson Laboratory, Dr. Shopland investigates the relationships between chromosome 3-dimensional (3D) structure and gene expression during mammalian development and tumorigenesis.
Primary Sequence Determines 3D Chromosome Architecture
One of Dr. Shopland's key discoveries is that the primary sequence (the linear order) of genomic elements on a chromosome dictates the chromosome's 3-D architecture. Her discovery stems from her research of the piebald deletion complex, a 5-megabase region on distal mouse Chromosome 14 (Mmu14) that contains multiple genes expressed during embryogenesis.
In nuclei where these genes are expressed, the piebald complex is folded into 3D structures that cluster several relatively distant genes together. The positions of the clustered genes depend on the primary sequence of the genes and gene deserts in the complex and likely mediate a variety of interactions among them. She and her team are investigating how these clusters form in differentiating cells.
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Sequence-based, dynamic model of chromosome region structure |
| Dynamic conformations in interphase nuclei structurally manage the complex genetic information within a gene-poor chromosome region. Arrayed gene clusters (blue) and deserts (gray) of 200 kb - 1 Mb act as building blocks for the formation of chromatin structures beyond the 30 nm fiber. Transient, probabilistic associations across a chromosome region, shown for gene clusters (dashed arrows), add up to predominant region conformations, such as (a) a relatively linear "striped fiber", (b) a "zig-zag" arrangement of gene clusters and deserts, and (c) a centralized "gene cluster hub" with closely aggregated gene clusters. Intermediate combinations of the patterns ("combo") further support dynamic transitions between one state and another (thick arrows). |
Nuclear Compartments May Mediate Chromosome Folding
Genomic sequences associate with distinct nuclear compartments, non membrane-bound regions which foster certain biochemical activities because they accumulate certain proteins and RNAs. Having discovered that the Mmu14 piebald complex organizes near a compartment containing the nuclear lamina and nuclear envelope, Dr. Shopland is investigating whether the 3D folding of the piebald complex is mediated by the nuclear lamina. She is collaborating with Dr. Leonard Shultz PhD of The Jackson Laboratory to test the effects of a lamin B receptor mutation in the icthyosis mouse, a model for Pelger-Huet anomaly, characterized by an altered distribution of heterochromatin.
Gene Deserts Modulate Gene Expression
Gene deserts contain sequences that regulate tissue-specific gene expression, perhaps by facilitating interactions between gene clusters and the nuclear periphery. The nuclear periphery associates with transcription factors and promotes the formation of heterochromatin, and its suspected role in gene regulation has been substantiated by Dr. Shopland's discovery that gene deserts in the Mmu14 gene clusters preferentially align with the nuclear periphery. Dr. Shopland's lab is collaborating with Dr. Carol Bult of The Jackson Laboratory to identify sequence elements that mediate association with the nuclear periphery. Additionally, Dr. Shopland is determining the locations of gene desert sequences and the genes they regulate to determine how they interact.
Chromosome Architecture in Lymphoma Cells
Dr. Shopland's discovery that primary sequence influences chromosome 3D structure is particularly relevant to cancer. Virtually all tumor cells harbor chromosome sequence rearrangements, which may have long-range "position effects" on many genes. She is collaborating with Kevin Mills PhD of The Jackson Laboratory to study chromosome rearrangements in a mouse model of progenitor B cell lymphoma, characterized by cancer cells with a recurrent translocation and a complex amplification of the c-myc (Myc) locus. She is testing how chromosome sequence rearrangements affect nuclear organization, chromosome folding, epigenetic mechanisms, and gene expression. The results of her studies may reveal targets for individualized cancer therapy.
Dr. Shopland's enthusiasm about her work is infectious. "I like to address questions that nobody else addresses, such as "What does a chromosome look like in 3 dimensions - if you could see a single gene - or all the genes - and all the other sequence in between?" I really love the excitement of a new discovery."
Reference
(Authors in bold are Jackson Laboratory Professors)
Shopland LS, Lynch CR, Peterson K, Thornton K, Kepper N, Stein S, Vincent S, Molloy K, Kreth G, Cremer C, Bult CJ, O'Brien TP. 2006. Folding and organization of a contiguous chromosome region according to the gene distribution pattern in primary genomic sequence. J Cell Biol 174: 27-38.
