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If induction tells cells what to do How do they remember these instructions for a lifetime?? Cloning: The ultimate Transplant experiment Dolly Cloning: The ultimate Transplant experiment Oops-Here’s the real Dolly (guess which tissue she was cloned from!) Cloning: The ultimate Transplant experiment So HOW does cloning work? Blastula stage cells Can be easily re-programmed But cloning success drops dramatically as the age of the nuclear donor increases Gilbert Fig. 4.6 But cloning success drops dramatically as the age of the nuclear donor increases Why?? Gilbert Fig. 4.6 All cells have the same DNA and thus the same library of genes yet different mRNAs are made by different cells Methylation is HERITABLE at the cell level and thus could be used by cells to remember decisions they have made ECB 3e 8-22 DNA imprinting: an example of how DNA methylation influences gene expression during development Two maternal genomes: “normal” embryo, Poor development of Extraembryonic tissue Two paternal genomes: Very small embryo, “normal” development of Extraembryonic tissue Imprinting results From pre-programmed Differences in DNA methylation Of selected genes in the sperm and egg The DNA within cells is NOT naked! Instead it is wrapped around histone proteins as chromatin Inactive genes are thought to be wrapped up in an inactive "chromatin conformation" Bone specific genes are wrapped up and inaccessible Skin cells Skin specific genes are not wrapped up and are thus accessible Muscle specific genes are wrapped up and inaccessible mRNA Gene expression Post-translational modification of histones plays a key role in regulating gene expression Post-translational modification of histones plays a key role in regulating gene expression To understand a third mechanism of large scale gene regulation, let’s return to this experiment If one transferred chromatin from a de-methylated fat cell that had become a myoblast it could tranform untreated fat cells. However frequency suggests Only one or a few of the genes have this ability They ultimately identified a single genemyoD - whose expression could convert ,any other cell types into muscle cells MyoD is induced by treatments that induce mesoderm MyoD is expressed at the right place and time to be a master regulator of muscle development But is this true??? Is myoD necessary for muscle formation? Mario Capecchi Oliver Smithies UNC Gene knockout Nobel prize in physiology and medicine 2007 Martin Evans MyoD works with related transcription factors to regulate the muscle cell fate MyoD works with related transcription factors to regulate the muscle cell fate I can tell you and even better story How to Remember a Developmental Decision Remember that Wingless is expressed by specific cells within each segment Engrailed is expressed by cells Anterior posterior to those that express Wingless Posterior Wg En Here’s the real thing Engrailed expression initially requires Wingless signaling by the neighboring cells Later, however, Engrailed becomes autoregulatory i.e., it turns on its own synthesis In cells where engrailed is turned off, a set of special chromatin proteins bind to it and wrap it up in a permanently inactive state. We also regulate stem cells And are mutated in cancer We also regulate stem cells And are mutated in cancer