iBiology Podcast

In his Part 3, Rutter emphasizes the challenge of mitochondrial protein synthesis. How do the components of the electron transport chain (ETC) assemble in the right stoichiometry at the right time? Rutter introduces the LYR family of proteins, which aid assembly of ETC components. LYR proteins interact with a common binding partner, the acyl carrier protein (ACP), via a unique fatty acyl moiety on ACP. Rutter’s group showed that ACP acylation is necessary for assembly of the ETC and activation of oxidative phosphorylation.

In Part 2 of his talk, Rutter describes his group’s work to unravel the relationship between the activity of the Mitochondrial Pyruvate Carrier (MPC) and the behavior of numerous cell types, including cancer and stem cells. His group found that forced expression of the MPC in multiple stem cell models led to reduced “stemness” and proliferative capacity, and that MPC inhibition could promote organoid formation in culture and tumor formation in vivo. These data indicate an important link between mitochondria, metabolism, and cell behavior.

Mitochondria are integral to the metabolism of eukaryotic cells, yet many of their properties are not fully understood. In Part 1 of this iBioSeminar, Dr. Jared Rutter lays out the foundational knowledge of mitochondrial structure and origin, and shares what is currently known about mitochondrial roles in metabolism, protein homeostasis, and signaling. He ends by highlighting a focus of his research group: to unravel the functions of uncharacterized mitochondrial proteins.

In his second talk, Peters presents evidence that cohesin is indeed necessary for genomic DNA to fold into loops. Long range DNA interactions such as loops can be detected using a technique called Hi-C. Using Hi-C, Peters shows that depleting cohesin removes DNA loops, while depleting the proteins that remove cohesin from DNA, results in bigger DNA loops. In addition, CTCF appears to recognize specific sequences that define the base of the loops.  Incorporating all of this data, Peters describes a model in which DNA is extruded by cohesin to form a loop and the boundaries of the loop are determined by CTCF. Peters explains that many questions about the mechanism of DNA loop extrusion and its importance in cells remain to be answered.

It has been known for many years that the protein cohesin is necessary to join sister chromatids together before they are segregated during mitosis.  Electron micrographs have shown that cohesin subunits form a ring complex which is thought to encircle the DNA keeping the chromatids together. When they need to separate during anaphase, the cohesin complex is removed by another set of proteins.  In his first talk, Dr. Peters explains how observations that he and others made suggested that cohesin may have additional roles in the cell. For instance, cohesin is initially loaded onto chromosome arms at discrete sites and in much larger amounts than is needed for chromatid cohesion. Cohesin also was shown to co-localize on chromosomes with a DNA binding protein called CTCF. CTCF is known to regulate transcription by forming DNA loops.  Peters explains that, taken together, these observations hinted at a role for cohesin and CTCF in folding DNA into loops to allow efficient packing of very large eukaryotic genomes into small cell nuclei, and regulating functions such as gene expression.

In his third talk, Patel explores the function of additional Hox genes in the development of crustacean body plans. Using CRISPR-Cas9 genome editing, his laboratory has characterized the expression and function of six of the nine Hox genes in Parhyale, and describes the combinatorial role of Ubx, abdA, and AbdB in the development of specialized appendages in this species, and how changes in the regulation of abdA is responsible for several morphological transitions during crustacean evolution.

In the second lecture, Patel describes the work of his lab to expand the studies of Hox gene function to other arthropods.  Patel describes the development of specialized body parts in crustaceans, and describes the transition between feeding to locomotor appendages. Using the beach hopper, Parhyale, his laboratory, in collaboration with the laboratory of Michalis Averof, showed that Ubx controls the boundary and transition between feeding and locomotor appendages during development.

Homeotic (Hox) genes are transcription factors that dictate the development and compartmentalization (regionalization) of body parts in animals along the anterior-posterior (head to tail) axis. Using various insects and crustaceans, Dr. Nipam Patel studies how alterations in the expression of Hox genes could explain the evolution of specialized body parts in arthropods. Patel describes the spatially restricted patterns of Hox gene expression, explains the effects of Hox gene deletions, and how these phenotypes help us understand the manner in which Hox genes act to control the insect body plan. Taking a closer look at the pattern of the Hox gene Ultrabithorax (Ubx) in different insects, Patel summarizes the discovery that what drives changes in the number of wings during insect evolution is the not changes in the expression pattern of Ubx, but the regulation of its downstream gene targets.

In her second seminar, Parast explains the different models to study human placental development in-vitro. Scientists can derive induced pluripotent stem cells (iPSCs) from umbilical cord cells. Parast’s laboratory first differentiates the iPSCs into trophoblasts cells which can then generate the different cells found in the placenta. Her laboratory uses these placental cells to study developmental complications by comparing cells derived from normal pregnancies to cells derived from non-normal pregnancies (e.g. patients born from mothers with pre-eclampsia).

Dr. Mana Parast provides an introduction to placental development, the organ that every mammalian embryo needs for proper growth and development. The placenta derives from trophoblasts, embryonic cells located in the outermost layer of the embryo. Pre-eclampsia and other maternal factors can hinder placental development and therefore affect the development of the fetus. A better understanding on how defects associated with pregnancy disorders affect placental development could lead to novel therapeutics in the future.