A National Cancer Institute-designated Comprehensive Cancer Center

Make an appointment: 800-826-HOPE
Singer-Sam, Judith, Ph.D. Laboratory Bookmark and Share

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 

Singer-Sam, Judith, Ph.D. Laboratory

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Research

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 
Our Scientists

Our research laboratories are led by the best and brightest minds in scientific research.
 

Beckman Research Institute of City of Hope is internationally  recognized for its innovative biomedical research.
City of Hope is one of only 41 Comprehensive Cancer Centers in the country, the highest designation awarded by the National Cancer Institute to institutions that lead the way in cancer research, treatment, prevention and professional education.
Learn more about City of Hope's institutional distinctions, breakthrough innovations and collaborations.
Develop new therapies, diagnostics and preventions in the fight against cancer and other life-threatening diseases.
 
Support Our Research
By giving to City of Hope, you support breakthrough discoveries in laboratory research that translate into lifesaving treatments for patients with cancer and other serious diseases.
 
 
 
 
NEWS & UPDATES
  • Cancer research has yielded scientific breakthroughs that offer patients more options, more hope for survival and a higher quality of life than ever before. The 14.5 million cancer patients living in the United States are living proof that cancer research saves lives. Now, in addition to the clinic, hospital an...
  • Advances in cancer treatment, built on discoveries made in the laboratory then brought to the bedside, have phenomenally changed the reality of living with a cancer diagnosis. More than any other time in history, people diagnosed with cancer are more likely to survive and to enjoy a high quality of life. Howeve...
  • While health care reform has led to an increase in the number of people signing up for health insurance, many people remain uninsured or are not taking full advantage of the health benefits they now have. Still others are finding that, although their premiums are affordable, they aren’t able to see the do...
  • Kidney cancer rates and thyroid cancer rates in adults have continued to rise year after year. Now a new study has found that incidence rates for these cancers are also increasing in children — particularly in African-American children. The study, published online this month in Pediatrics, examined childhood ca...
  • Thyroid cancer has become one of the fastest-growing cancers in the United States for both men and women. The chance of being diagnosed with the cancer has nearly doubled since 1990. This year an estimated 63,000 people will be diagnosed with thyroid cancer in the United States and nearly 1,900 people will die ...
  • Older teenagers and young adults traditionally face worse outcomes than younger children when diagnosed with brain cancer and other central nervous system tumors. A first-of-its-kind study shows why. A team of researchers from the departments of Population Sciences and Pathology at City of Hope recently examine...
  • Cancer treatment can take a toll on the mouth, even if a patient’s cancer has nothing to do with the head or throat, leading to a dry mouth, or a very sore mouth, and making it difficult to swallow or eat. Here’s some advice from the National Cancer Institute (NCI)  on how to ease cancer-related dis...
  • Radiation oncology is one of the three main specialties involved in the successful treatment of cancer, along with surgical oncology and medical oncology. Experts in this field, known as radiation oncologists, advise patients as to whether radiation therapy will be useful for their cancer – and how it can best ...
  • There’s more to cancer care than simply helping patients survive. There’s more to cancer treatment than simple survival. Constant pain should not be part of conquering cancer,  insists Betty Ferrell, Ph.D., R.N., director of nursing research and education at City of Hope. She wants patients and caregivers...
  • Even its name is daunting. Systemic mastocytosis is a fatal disease of the blood with no known cure. But a new study suggests a bone marrow transplant may be the answer for some patients. While rare, systemic mastocytosis is resistant to treatment with drugs and, when aggressive, can be fatal within four years ...
  • Could what you eat affect the health of your chromosomes? The short answer is, “Yes.” Researchers led by Dustin Schones, Ph.D., assistant professor in the Department of Cancer Biology, and Rama Natarajan, Ph.D., director of the Division of Molecular Diabetes Research and the National Business Products Industry ...
  • September is Prostate Cancer Awareness Month. Here, Bertram Yuh, M.D., assistant clinical professor in the Division of Urology and Urologic Oncology at City of Hope, explains the importance of understanding the risk factors for the disease and ways to reduce those risks, as well as overall prostate health. “Wha...
  • ** Learn more about prostate health, plus prostate cancer research and treatment, at City of Hope. ** Learn more about getting a second opinion at City of Hope by visiting us online or by calling 800-826-HOPE (4673). City of Hope staff will explain what’s required for a consult at City of Hope and help yo...
  • Childhood cancer survival rates have increased dramatically over the past 40 years. More than 80 percent of children with cancer now survive five years or more, which is a tremendous feat. Despite the survival rate increase, cancer continues to be the No. 1 disease killer and second-leading cause of death in ch...
  • Although a stem cell transplant can be a lifesaving procedure for people diagnosed with a blood cancer or blood disorder, the standard transplant may not be appropriate for all patients. This is because the conditioning regimen (the intensive chemotherapy and/or radiation treatments preceding the transplant) is...