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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Developmental biology - Human Genome Atlas

Atlas of the human genome using stem cells

A new human gene atlas reveals some surprises...


Scientists from the Hebrew University of Jerusalem have generated an atlas of the human genome showing how all genes make up the human body. Using a state-of-the-art gene editing technology on human embryonic stem cells, their process illuminates how genes affect our health and disease origins. The work appears in the journal Nature Cell Biology.
Embryonic stem cells are a unique resource as they can turn into any adult cell in our body. Their versatility makes them the focus in regenerative medicine, disease modeling and drug discovery.

In parallel to the discovery of human embryonic stem cells, another milestone in biology was completed with the sequencing of the human genome by NHGRI in April 2003, and the identification of the entire set of genes responsible for our human identity.

Sequencing the human genome led to the challenge of understanding how our genes function. This new study from Hebrew University provides a novel tool to map all human gene function by using human embryonic stem cells (hESCs).

Researchers did this by analyzing virtually all of the genes in our genome, generating more than 180,000 distinct mutations. To produce such a vast array of mutations, they combined the gene-editing technology of CRISPR-Cas9 screening with a new type of embryonic stem cell recently isolated by the same research group. This newly generated stem cell has only a single copy of the human genome, instead of two copies — one from the mother and one from the father — reducing gene editing to one copy for each gene.
Researchers can now see that a mere 9% of all genes in the human genome are essential to the growth and survival of human embryonic stem cells — and 5% of those actually limit the growth of these cells. They can now analyze the role of genes responsible for all hereditary disorders in early human development and growth. Furthermore, they can see how cancer-causing genes might affect the growth of the human embryo.

"This gene atlas enables a new functional view on how we study the human genome and provides a tool that will change the fashion by which we analyze and treat cancer and genetic disorders," says Nissim Benvenisty MD, PhD, Director, Azrieli Center for Stem Cells and Genetic Research, the Herbert Cohn Chair in Cancer Research, Hebrew University of Jerusalem, and senior author of the study.
A key finding is the identification of a small group of genes uniquely essential to survival of human embryonic stem cells (hESCs), appearing to maintain their identity and prevent them from becoming cancers or turning into adult cells.

"This study creates a new framework in understanding what it means to be an embryonic stem cell at the genetic level. The more complete a picture we have of the nature of these cells, the better chances we have for successful therapies in the clinic," adds Dr. Atilgan Yilmaz PhD, postdoctoral fellow, and a lead author.

Abstract
The maintenance of pluripotency requires coordinated expression of a set of essential genes. Using our recently established haploid human pluripotent stem cells (hPSCs), we generated a genome-wide loss-of-function library targeting 18,166 protein-coding genes to define the essential genes in hPSCs. With this we could allude to an intrinsic bias of essentiality across cellular compartments, uncover two opposing roles for tumour suppressor genes and link autosomal-recessive disorders with growth-retardation phenotypes to early embryogenesis. hPSC-enriched essential genes mainly encode transcription factors and proteins related to cell-cycle and DNA-repair, revealing that a quarter of the nuclear factors are essential for normal growth. Our screen also led to the identification of growth-restricting genes whose loss of function provides a growth advantage to hPSCs, highlighting the role of the P53–mTOR pathway in this context. Overall, we have constructed an atlas of essential and growth-restricting genes in hPSCs, revealing key aspects of cellular essentiality and providing a reference for future studies on human pluripotency.

Authors: Atilgan Yilmaz, Mordecai Peretz, Aviram Aharony, Ido Sagi & Nissim Benvenisty.


Acknowledgements: The authors thank E. Meshorer and all members of The Azrieli Center for Stem Cells and Genetic Research for their input and critical reading of the manuscript. The authors also thank O. Yanuka, T. Golan-Lev and A. Petcho for assistance with tissue culture. This work was partially supported by the US–Israel Binational Science Foundation (grant no. 2015089), by the Israel Science Foundation (grant no. 494/17) and by the Azrieli Foundation. A.Y. is supported by the Lady Davis Postdoctoral Fellowship. I.S. is supported by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities, and N.B. is the Herbert Cohn Chair in Cancer Research.

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May 15, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Haploid human embryonic stem cells. Image credit: Azrieli Center for Stem Cells and Genetic Research, Hebrew University, Jerusalem.


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